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US20240376128A1 - N-cyclopropylpyrido [4, 3-d] pyrimidin-4-amine derivatives and uses thereof - Google Patents

N-cyclopropylpyrido [4, 3-d] pyrimidin-4-amine derivatives and uses thereof Download PDF

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Publication number
US20240376128A1
US20240376128A1 US18/684,203 US202218684203A US2024376128A1 US 20240376128 A1 US20240376128 A1 US 20240376128A1 US 202218684203 A US202218684203 A US 202218684203A US 2024376128 A1 US2024376128 A1 US 2024376128A1
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Prior art keywords
alkyl
membered
haloc
alkenyl
alkynyl
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US18/684,203
Inventor
Hongwei Yang
Cunbo Ma
Panliang GAO
Huifeng Han
Peng Wang
Runze LI
Xiaoyu Liu
Yanping Wang
Wei Long
Wei Zhang
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Jacobio Pharmaceuticals Co Ltd
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Jacobio Pharmaceuticals Co Ltd
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Assigned to JACOBIO PHARMACEUTICALS CO., LTD. reassignment JACOBIO PHARMACEUTICALS CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GAO, Panliang, HAN, Huifeng, LI, Runze, LIU, XIAOYU, LONG, Wei, MA, CUNBO, WANG, PENG, WANG, YANPING, YANG, HONGWEI, ZHANG, WEI
Publication of US20240376128A1 publication Critical patent/US20240376128A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention relates to compounds that inhibit the activity of multiple forms of K-Ras protein including K-Ras wild type and K-Ras mutant types, compositions comprising the same, and the methods of using the same.
  • K-Ras Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • GDP-bound inactive
  • GTP-bound active
  • Aberrant expression of K-Ras accounts for up to ⁇ 20% of all cancers and oncogenic K-Ras mutations that stabilize GTP binding and lead to constitutive activation of K-Ras.
  • K-Ras mutations at codons 12, 13, 61 and other positions of the K-Ras primary amino acid sequence are present in 88% of all pancreatic adenocarcinoma patients, 50% of all colorectal adenocarcinoma patients, and 32% lung adenocarcinoma patients.
  • a recent publication also suggested wild type K-Ras inhibition could be a viable therapeutic strategy to treat K-Ras wild type dependent cancers.
  • Allele-specific K-Ras G12C inhibitors such as sotorasib (AMG510) or adagrasib (MRTX849), are currently changing the treatment paradigm for patients with K-Ras G12C mutated non-small cell lung cancer and colorectal cancer.
  • sotorasib AMG510
  • MRTX849 adagrasib
  • K-Ras inhibitors have the potential to address broad patient populations, including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant and K-Ras wild type amplified cancers.
  • composition comprising a therapeutically effective amount of a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof as defined herein; and a pharmaceutically acceptable excipient.
  • Also provided herein is a method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein to a subject in need thereof.
  • a compound of Formula (IB) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein to a subject in need thereof.
  • a compound of Formula (IB) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof
  • Also provided herein is a process for preparing a compound of Formula (IB) as defined herein.
  • R 2a is selected from hydrogen, deuterium, —C 1-6 alkyl, haloC 1-6 alkyl, —C 1-6 alkoxy, —C( ⁇ O)C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S( ⁇ O) or S( ⁇ O) 2 , phenyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; wherein said —C 1-6 alkyl, haloC 1-6 alkyl, —C 1-6 alkoxy, —C( ⁇ O)C 1-6 alkyl, 3-6 membered cycl
  • R 2a is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, iso-hexyl, sec-hexyl, tert-hexyl, halomethyl, haloethyl, methoxy, ethoxy, —C( ⁇ O)CH 3 , —C( ⁇ O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopent
  • R S1 at each occurrence is independently selected from deuterium, halogen, —C 1-6 alkyl, haloC 1-6 alkyl, —CN, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —OH, —OC 1-3 alkyl, —SH, —SC 1-3 alkyl, —C( ⁇ O)C 1-3 alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1-3 alkyl, —OC( ⁇ O)C 1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; wherein said
  • 3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more substitutents selected from deuterium, halogen, —C 1-6 alkyl, haloC 1-6 alkyl, —CN, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —OH, —OC 1-3 alkyl, —SH, —SC 1-3 alkyl, —C( ⁇ O)C 1-3 alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1-3 alkyl, —OC( ⁇ O)C 1-3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
  • R S1 at each occurrence is independently selected from deuterium, —F, —Cl, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, iso-hexyl, sec-hexyl, tert-hexyl, halomethyl, haloethyl, —CN, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —OH, methoxy, eth
  • R S1 at each occurrence is independently selected from -D, —F, —CH 3 , —CD 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, —CH 2 CN, —OH, —OCH 3 , —OCD 3 , —NHCH 3 , —SCH 3 , —CH 2 OCH 3 , —C( ⁇ O)CH 3 , —CH 2 CH 3 , —CHFCF 3 ,
  • R S1 linked with the carbon atom indicated with ** and NR 2a linked with the carbon atom indicated with * are in a trans configuration
  • R S5 at each occurrence is independently selected from deuterium, halogen, —C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, —C 2-3 alkenyl, —CN, —N(R 66 ) 2 , —OR 66 , —SR 66 , —C( ⁇ O)R 67 , —C( ⁇ O)OR 66 , —OC( ⁇ O)R 67 , —C( ⁇ O)N(R 66 ) 2 , —NR 66 C( ⁇ O)R 67 , —OC( ⁇ O)OR 66 , —NR 66 C( ⁇ O)OR 66 , —NR 66 C( ⁇ O)OR 66 , —NR 66 C( ⁇ O)OR 66 , —NR 66 C( ⁇ O)OR 66 , —NR 66 C( ⁇ O)OR 66 , —NR 66 C( ⁇ O)OR
  • —C 1-6 alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, halogen, —C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, —CN, oxo, —N(R 68 ) 2 , —OR 68 , —C( ⁇ O)R 68 , —C( ⁇ O)OR 68 , —OC( ⁇ O)R 68 , —C(—)NR 68 ) 2 , —NR 68 C( ⁇ O)R 69 , —OC( ⁇ O)OR 68 , —NR 68 C( ⁇ O)OR 69 , —OC( ⁇ O)N(R 68 ) 2 , —OC( ⁇ S)N(R 68 ) 2 , —NR 68 C( ⁇ O)N(R 68 ) 2 , —NR 68 S( ⁇ O) 2 R 69 , 3-6 member
  • R S5 at each occurrence is independently selected from deuterium, —F, —C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, —C 2-6 alkenyl, —C 2-6 alkynyl, —CN, —N(R 66 ) 2 , —OR 66 , —SR 66 , —C( ⁇ O)R 67 , —C( ⁇ O)OR 66 , —OC( ⁇ O)R 67 , —C( ⁇ O)N(R 66 ) 2 , —NR 66 C( ⁇ O)R 67 , —OC( ⁇ O)OR 66 , —NR 66
  • R S5 at each occurrence is independently selected from deuterium, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH ⁇ CH 2 , —C ⁇ CH, —C ⁇ CCH 3 , —C ⁇ CD, —CH 2 C ⁇ CH, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CH 2 CH 2 CH 2 F, —OH, —CH 2 OH, —CH 2 CH 2 OH, —OCH 3 , —OC(CH 3
  • each moiety in the Table 6 is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R 41 .
  • R 41 is independently selected from —F, —Cl, —C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, —C 2-3 alkenyl, —C 2-3 alkynyl, —CN, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —OH, —O(C 1-3 alkyl), —SH, —S(C 1-3 alkyl), —S( ⁇ O)H, —S( ⁇ O)(C 1-3 alkyl), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein said —C 1-3 alkyl,
  • R 51 is selected from hydrogen, deuterium, —F, —Cl, —Br, —C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, —CN, —NHC 1-3 alkyl, —N(C 1-3 alkyl) 2 , —OC 1-3 alkyl, —O-(3-6 membered cycloalkyl), —SC 1-3 alkyl, —S(haloC 1-3 alkyl) or 3-6 membered cycloalkyl; wherein, said —C 1-3 alkyl or 3-6 membered cycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from halogen
  • R 51 is selected from hydrogen, deuterium, —Cl, —CN, —CH 3 , —CHF 2 , —CH 2 F, —CF 3 , —CH 2 OH, —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —SCH 3 , —NHCH 3 , —N(CH 3 ) 2 , —OCF 3 , —CN, —CH 2 CN, —COOH, —CONH 2 , —COOCH 3 ,
  • R 43 at each occurrence is independently selected from
  • R 4c is selected from hydrogen, —C 1-30 alkyl, —C 2-30 alkenyl, —C 2-30 alkynyl, —C 0-6 alkylene-(3-20 membered carbocyclyl), —C 0-6 alkylene-(3-20 membered heterocyclyl), —C 0-6 alkylene-(6-10 membered aryl) or —C 0-6 alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R 4j ;
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [36], and a pharmaceutically acceptable excipient.
  • a method for treating cancer in a subject comprising administering a therapeutically effective amount of the compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [36], or the pharmaceutical composition of [37] to a subject in need thereof.
  • a method for treating cancer in a subject in need thereof comprising:
  • halogen or “halo”, as used interchangeably herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include —F, —Cl and —Br.
  • alkyl refers to saturated monovalent hydrocarbon radicals having straight or branched arrangement.
  • C 1-10 in —C 1-10 alkyl is defined to identify the group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in a linear or branched arrangement.
  • Non-limiting alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • haloalkyl refers to the above-mentioned alkyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as —F, —Cl or —Br).
  • the haloalkyl is interchangeable —C 1-10 haloalkyl or haloC 1-10 alkyl, wherein, C 1-10 in the —C 1-10 haloaklyl or haloC 1-10 alkyl indicates that the total carbon atoms of the alkyl are 1 to 10.
  • the —C 1-10 haloalkyl is the —C 1-6 haloalkyl.
  • the —C 1-6 haloalkyl is the —C 1-3 haloalkyl.
  • the —C 1-3 haloalkyl is (methyl, ethyl, propyl or isopropyl) substituted with 1, 2, 3, 4, 5, or 6 —F; preferably, the —C 1-3 haloalkyl is —CF 3 .
  • alkylene refers to a divalent group obtained by removal of an additional hydrogen atom from an alkyl group defined above.
  • the alkylene is C 0-6 alkylene.
  • the C 0-6 alkylene is C 0-3 alkylene. The C 0-6 in the front of the alkylene indicates the total carbon atoms in the alkylene are 0 to 6 and C 0 indicates the two ends of the alkylene are connected directly.
  • Non-limiting alkylene includes methylene (i.e., —CH 2 —), ethylene (i.e., —CH 2 —CH 2 — or —CH(CH 3 )—) and propylene (i.e., —CH 2 —CH 2 —CH 2 —, —CH(—CH 2 —CH 3 )— or —CH 2 —CH(CH 3 )—).
  • alkenyl refers to a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
  • the alkenyl is —C 2-10 alkenyl. In some embodiments, the —C 2-10 alkenyl is —C 2-6 alkenyl which contains from 2 to 6 carbon atoms.
  • Non-limiting alkenyl includes ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
  • haloalkenyl refers to the above-mentioned alkenyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as —F, —Cl or —Br).
  • the haloalkenyl is interchangeable —C 2-10 haloalkenyl or haloC 2-10 alkenyl, wherein, C 2-10 in the —C 2-10 haloaklenyl or haloC 2-10 alkenyl indicates that the total carbon atoms of the alkenyl are 2 to 10.
  • the —C 2-10 haloalkenyl is the —C 2-6 haloalkenyl. In some embodiments, the —C 2-6 haloalkenyl is the —C 2-3 haloalkenyl. In some embodiments, the —C 2-3 haloalkenyl is (ethenyl or propenyl) substituted with 1, 2, 3, 4, 5, or 6 —F.
  • alkynyl refers to a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
  • the alkynyl is —C 2-10 alkynyl.
  • the —C 2-10 alkynyl is —C 2-6 alkynyl which contains from 2 to 6 carbon atoms.
  • Non-limiting alkynyl includes ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • haloalkynyl refers to the above-mentioned alkynyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as —F, —Cl or —Br).
  • the haloalkynyl is interchangeable —C 2-10 haloalkynyl or haloC 2-10 alkynyl, wherein, C 2-10 in the —C 2-10 haloaklynyl or haloC 2-10 alkynyl indicates that the total carbon atoms of the alkynyl are 2 to 10.
  • the —C 2-10 haloalkynyl is the —C 2-6 haloalkynyl. In some embodiments, the —C 2-6 haloalkynyl is the —C 2-3 haloalkynyl. In some embodiments, the —C 2-3 haloalkynyl is (ethynyl or propynyl) substituted with 1, 2, 3, 4, 5, or 6 —F.
  • alkoxy refers to oxygen ethers formed from the previously described alkyl groups.
  • haloalkoxy refers to the above-mentioned alkoxy substituted with one or more (for 1, 2, 3, 4, 5, or 6) halogen (—F, —Cl or —Br).
  • the haloalkoxy is interchangeable —C 1-10 haloalkoxy or haloC 1-10 alkoxy.
  • the haloalkoxy is interchangeable —C 1-6 haloalkoxy or haloC 1-6 alkoxy, wherein, C 1-6 in the —C 1-6 haloakloxy or haloC 1-6 alkoxy indicates that the total carbon atoms of the alkoxy are 1 to 6.
  • the —C 1-6 haloalkoxy is the —C 1-3 haloalkoxy.
  • the —C 1-3 haloalkoxy is (methoxy, ethoxy, propoxy or isopropoxy) substituted with 1, 2, 3, 4, 5, or 6 —F; preferably, the —C 1-3 haloalkoxy is —OCF 3 .
  • carrier refers to a totally saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring only containing carbon atoms as ring members.
  • carrier as used herein, unless otherwise indicated, means a monovalent group obtained by removal of a hydrogen atom on the ring carbon atom from the carbocyclic ring defined in the present invention.
  • the carbocyclic ring is interchangeable with the carbocyclyl ring in the present invention.
  • the carbocyclic ring is a three to twenty membered (such as 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-membered) carbocyclic ring and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, one, two, three, four, five or six, are included within the present definition.
  • the carbocyclic ring includes a cycloalkyl ring in which all ring carbon atoms are saturated, a cycloalkenyl ring which contains at least one double bond (preferred contain one double bond), and a cycloalkynyl ring which contains at least one triple bond (preferred contain one triple bond).
  • Cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • Cycloalkenyl includes but not limited to cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like.
  • the carbocyclyl ring includes a monocyclic carbocyclyl ring, and a bicyclic or polycyclic carbocyclyl ring in which one, two or three or more atoms are shared between the rings.
  • the term “spirocyclic carbocyclic ring” refers to a carbocyclic ring in which each of the rings only shares one ring atom with the other ring.
  • the spirocyclic ring is bicyclic spirocyclic ring.
  • the spirocyclic carbocyclic ring includes a spirocyclic cycloalkyl ring and a spirocyclic cycloalkenyl ring and a spirocyclic cycloalkynyl ring.
  • the term “fused carbocyclic ring” refers to a carbocyclic ring in which each of the rings shares two adjacent ring atoms with the other ring.
  • the fused ring is a bicyclic fused ring.
  • the fused carbocyclic ring includes a fused cycloalkyl ring and a fused cycloalkenyl ring and a fused cycloalkynyl ring.
  • a monocyclic carbocyclic ring fused with an aromatic ring (such as phenyl) is included in the definition of the fused carbocyclic ring.
  • the term “bridged carbocyclic ring” refers to a carbocyclic ring that includes at least two bridgehead carbon ring atoms and at least one bridging carbon atom. In some embodiments, the bridged ring is bicyclic bridged ring.
  • the bridged carbocyclic ring includes a bicyclic bridged carbocyclic ring which includes two bridgehead carbon atoms and a polycyclic bridged carbocyclic ring which includes more than two bridgehead carbon atoms.
  • the bridged carbocyclic ring includes a bridged cycloalkyl ring, a bridged cycloalkenyl ring and a bridged cycloalkynyl ring.
  • Examples of monocyclic carbocyclyl and bicyclic carbocyclyl include but not limit to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
  • heterocyclic ring refers to a totally saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring containing not only carbon atoms as ring members and but also containing one or more (such as 1, 2, 3, 4, 5, or 6) heteroatoms as ring members.
  • Preferred heteroatoms include N, O, S, N-oxides, sulfur oxides, and sulfur dioxides.
  • heterocyclyl as used herein, unless otherwise indicated, means a monovalent group obtained by removal of a 50 hydrogen atom on the ring carbon atom or the ring heteroatom from the heterocyclic ring defined in the present invention.
  • the heterocyclic ring is interchangeable with the heterocyclyl ring in the present invention.
  • the heterocyclic ring is a three to twenty membered (such as 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-membered) heterocyclic ring and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, one, two, three, four, five or six, 55 are included within the present definition.
  • the heterocyclic ring includes a heterocycloalkyl ring in which all ring carbon atoms are saturated, a heterocycloalkenyl ring which contains at least one double bond (preferred contain one double bond), and a heterocycloalkynyl ring which contains at least one triple bond (preferred contain one triple bond).
  • the heterocyclyl ring includes a monocyclic heterocyclyl ring, and a bicyclic or polycyclic heterocyclyl ring in which one, two or three or more atoms are shared between the rings.
  • the term “spirocyclic heterocyclic ring” refers to a heterocyclic ring in which each of the rings only shares one ring atom with the other ring.
  • the spirocyclic ring is bicyclic spirocyclic ring.
  • the spirocyclic heterocyclic ring includes a spirocyclic heterocycloalkyl ring and a spirocyclic heterocycloalkenyl ring and a spirocyclic heterocycloalkynyl ring.
  • the term “fused heterocyclic ring” refers to a heterocyclic ring in which each of the rings shares two adjacent ring atoms with the other ring.
  • the fused ring is a bicyclic fused ring.
  • the fused heterocyclic ring includes a fused heterocycloalkyl ring and a fused heterocycloalkenyl ring and a fused heterocycloalkynyl ring.
  • a monocyclic heterocyclic ring fused with an aromatic ring (such as phenyl) is included in the definition of the fused heterocyclic ring.
  • the term “bridged heterocyclic ring” refers to a heterocyclic ring that includes at least two bridgehead ring atoms and at least one bridging atom. In some embodiments, the bridged ring is bicyclic bridged ring.
  • the bridged heterocyclic ring includes a bicyclic bridged heterocyclic ring which includes two bridgehead atoms and a polycyclic bridged heterocyclic ring which includes more than two bridgehead atoms.
  • the bridged heterocyclic ring includes a bridged heterocycloalkyl ring, a bridged heterocycloalkenyl ring and a bridged heterocycloalkynyl ring.
  • heterocyclyl examples include but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
  • aryl refers to a mono or polycyclic aromatic ring system only containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic rings. Phenyl and naphthyl are preferred aryls.
  • heteroaryl refers to an aromatic ring containing carbons and one or more (such as 1, 2, 3 or 4) heteroatoms selected from N, O or S.
  • the heteroaryl may be monocyclic or polycyclic.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 heteroatoms.
  • a polycyclic heteroaryl ring may contain fused ring junction, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms), preferred monocyclic heteroaryl is 5 membered heteroaryl including 1, 2, 3 or 4 heteroatoms selected from N, O or S, or 6 membered heteroaryl including 1 or 2 heteroatoms selected from N.
  • heteroaryl groups include, but not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl or isoquinolinyl.
  • one or more refers to one or more than one. In some embodiments, “one or more” refers to 1, 2, 3, 4, 5 or 6. In some embodiments, “one or more” refers to 1, 2, 3 or 4. In some embodiments, “one or more” refers to 1, 2, or 3. In some embodiments, “one or more” refers to 1 or 2. In some embodiments, “one or more” refers to 1. In some embodiments, “one or more” refers to 2. In some embodiments, “one or more” refers to 3. In some embodiments, “one or more” refers to 4. In some embodiments, “one or more” refers to 5. In some embodiments, “one or more” refers to 6.
  • substituted refers to a hydrogen atom on the carbon atom or a hydrogen atom on the nitrogen atom is replaced by a substituent.
  • substituents When one or more substituents are substituted on a ring in the present invention, it means that each of substituents may be respectively independently substituted on every ring atom of the ring including but not limited to a ring carbon atom or a ring nitrogen atom.
  • the ring is a polycyclic ring, such as a fused ring, a bridged ring or a spiro ring, each of substituents may be respectively independently substituted on every ring atom of the polycyclic ring.
  • oxo refers to oxygen atom together with the attached carbon atom forms the group.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds in the present invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).
  • the present invention includes within its scope the prodrug of the compounds of this invention.
  • such prodrug will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and configuration isomers.
  • the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
  • the invention includes all possible stereoisomers of the compound.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the isotopes of hydrogen can be denoted as 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). They are also commonly denoted as D for deuterium and T for tritium.
  • CD 3 denotes a methyl group wherein all of the hydrogen atoms are deuterium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
  • deuterated derivative refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom (“D”). It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivative described herein.
  • the deuterated derivative of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5% deuterium incorporation at each designated deuterium) at least 4500, (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation) at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at lease 6333.3 (95% deuterium incorporation, at least 6466.7 (97% deuterium incorporation, or at least 6600 (99% deuterium incorporation).
  • the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • conjugated form refers to herein that the compound described herein is conjugated to another agent through a linker or not through a linker, wherein, the compound functions as a binder or a inhibitor of K-Ras protein (including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant protein and K-Ras wild type protein)
  • the conjugated form is a PROTAC molecule, e.g. the compound is incorporated into proteolysis targeting chimeras (PROTACs).
  • a PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used.
  • the portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms.
  • variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis.
  • compositions of the present invention comprise a compound in present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof as defined herein can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound in the present invention or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt.
  • the compounds of the present invention or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound in the present invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • subject refers to an animal.
  • the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a human.
  • a “patient” as used herein refers to a human subject.
  • a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the subject has experienced and/or exhibited at least one symptom of cancer to be treated and/or prevented.
  • the subject has been identified or diagnosed as having a cancer having wild type K-Ras or a K-Ras G12A, K-Ras G12C, K-Ras G12D, K-Ras G12R, K-Ras G12S, K-Ras G12V, K-Ras G13D and/or K-Ras Q61H mutation
  • inhibitor refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • treat refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • K-Ras G12A refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an alanine for a glycine at amino acid position 12.
  • a “K-Ras G12A inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12A.
  • a “K-Ras G12A associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12A mutation.
  • K-Ras G12C refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
  • a “K-Ras G12C inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12C.
  • K-Ras G12C associated cancer refers to a cancer associated with or mediated by or having a K-Ras G12C mutation.
  • K-Ras G12D refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12.
  • a “K-Ras G12D inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12D.
  • a “K-Ras G12D associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12D mutation.
  • K-Ras G12R refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an arginine for a glycine at amino acid position 12.
  • a “K-Ras G12R inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12R.
  • a “K-Ras G12R associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12R mutation.
  • K-Ras G12S refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12.
  • a “K-Ras G12S inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12S.
  • K-Ras G12S associated cancer refers to a cancer associated with or mediated by or having a K-Ras G12S mutation.
  • K-Ras G12V refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a valine for a glycine at amino acid position 12.
  • a “K-Ras G12V inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12V.
  • K-Ras G12V associated cancer refers to a cancer associated with or mediated by or having a K-Ras G12V mutation.
  • K-Ras G13D refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 13.
  • a “K-Ras G13D inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G13D.
  • a “K-Ras G13D associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G13D mutation.
  • K-Ras Q61H refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a histidine for a glutamine at amino acid position 61.
  • a “K-Ras Q61H inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras Q61H.
  • a “K-Ras Q61H associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras Q61H mutation.
  • the crude product was purified by Pre-HPLC with the following condition (Daisogel C18, 50 mm ⁇ 250 mm, 10 um; A: 0.1% TFA in water, B: CH 3 CN, Gradient: 15% B to 59% B in 48 min at a flow rate of 60 mL/min, 265 nm) and freeze-dried to give Compound 28 (TFA salt, 44.1 mg, 21.69% yield). MS: m/z: 664[M+H] + .
  • the crude product was purified by Pre-HPLC with the following condition (Daisogel C18, 50 mm ⁇ 250 mm, 10 um; A: 0.1% TFA in water, B: CH 3 CN, Gradient: 15% B to 50% B in 40 min at a flow rate of 60 mL/min, 245 nm) and freeze-dried to give Compound 29 (TFA salt, 162.2 mg, 25.30% yield). MS: m/z: 720[M+H] + .
  • the crude product was purified by Pre-HPLC with the following condition (Daisogel C18, 50 mm ⁇ 250 mm, 10 um; A: 0.1% TFA in water, B: CH 3 CN, Gradient: 15% B to 55% B in 50 min at a flow rate of 60 mL/min, 235 nm and freeze-dried to give Compound 30 (TFA salt, 70.5 mg, 20.66% yield). MS: m/z: 774[M+H] + .
  • the crude product was purified by Pre-HPLC with the following condition (Agela Durashell C18, 30 mm ⁇ 250 mm, 10 um; A: 0.1% TFA in water, B: CH 3 CN, Gradient: 15% B to 49% B in 37 min at a flow rate of 40 mL/min, 240 nm) and freeze-dried to give Compound 31 (TFA salt, 57.1 mg, 39.96% yield). MS: m/z: 836[M+H] + .
  • K-Ras G12D K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WI proteins were used in this assay.
  • K-Ras His tag, aa 1-169 pre-loaded with GDP was pre-incubated with each of compounds in the presence of 10 nM GDP in a 384-well plate (Greiner) for 15-60 mins, then purified SOS1 Ext (Flag tag, aa 564-1049), BODIPYTM FL GTP (Invitrogen) and monoclonal antibody anti 6HIS—Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 4 hours at 25° C. (Specially, we did not add SOS1 in the K-Ras G13D assay).
  • GppNp is an analog of GTP.
  • K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WI proteins were used in this assay.
  • K-Ras His tag, aa 1-169 pre-loaded with GppNp was pre-incubated with each of compounds in the presence of 200 ⁇ M GTP in a 384-well plate (Greiner) for 15-60 mins, then cRAF RBD (GST tag, aa 50-132, CreativeBioMart), monoclonal antibody anti GST-d2 (Cisbio) and monoclonal antibody anti 6HIS—Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 2 hours at 25° C. Wells containing same percent of DMSU served as vehicle control, and wells without K-Ras served as low control. HTRP signals were read on Tecan Spark multimode microplate reader and HTRF ratios were calculated under manufacturer's instructions.
  • MKN-1 with K-Ras WT amplification is also a K-Ras dependent cell line.
  • Mice in group A were treated with a single 3 mg/kg dose of compound (iv).
  • Mice in group B were treated with a single 10 mg/kg dose of compound (po).
  • blood samples were collected at the time point of 0.083, 0.5, 1, 2, 4 and 8 h post-dose.
  • For each mouse in group B blood samples were collected at the time point of 0.5, 1, 2, 4, 6 and 8 h post-dose. Blood samples were placed on ice until centrifugation to obtain plasma samples. The plasma samples were stored at ⁇ 80° C. until analysis. The concentration of compound in plasma samples was determined using a LC-MS/MS method. The results are shown in the following Table 22.

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Abstract

Provided herein is a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof; composition containing the same and the use thereof.
Figure US20240376128A1-20241114-C00001

Description

    CROSS-REFERENCES TO RELATED APPLICATIONS
  • This application claims the benefit of priority to PCT/CN2021/113365, filed on Aug. 18, 2021; PCT/CN2021/132066, filed on Nov. 22, 2021; PCT/CN2021/132636, filed on Nov. 24, 2021; PCT/CN2021/139165, filed on Dec. 17, 2021; PCT/CN2022/072459, filed on Jan. 18, 2022; PCT/CN2022/072926, filed on Jan. 20, 2022; PCT/CN2022/074053, filed on Jan. 26, 2022; PCT/CN2022/074165, filed on Jan. 27, 2022; PCT/CN2022/077674, filed on Feb. 24, 2022; PCT/CN2022/081602, filed on Mar. 18, 2022; PCT/CN2022/083320, filed on Mar. 28, 2022; PCT/CN2022/084317, filed on Mar. 31, 2022 and PCT/CN2022/087377, filed on Apr. 18, 2022, all of which are hereby incorporated herein by reference in their entireties.
    • TECHNICAL FIELD
  • The invention relates to compounds that inhibit the activity of multiple forms of K-Ras protein including K-Ras wild type and K-Ras mutant types, compositions comprising the same, and the methods of using the same.
    • BACKGROUND ART
  • Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“K-Ras”) is a small GTPase and a member of the RAS family of oncogenes. K-Ras serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation. Aberrant expression of K-Ras accounts for up to ˜20% of all cancers and oncogenic K-Ras mutations that stabilize GTP binding and lead to constitutive activation of K-Ras. K-Ras mutations at codons 12, 13, 61 and other positions of the K-Ras primary amino acid sequence are present in 88% of all pancreatic adenocarcinoma patients, 50% of all colorectal adenocarcinoma patients, and 32% lung adenocarcinoma patients. A recent publication also suggested wild type K-Ras inhibition could be a viable therapeutic strategy to treat K-Ras wild type dependent cancers.
  • Allele-specific K-Ras G12C inhibitors, such as sotorasib (AMG510) or adagrasib (MRTX849), are currently changing the treatment paradigm for patients with K-Ras G12C mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive K-Ras allele has fueled drug discovery efforts for all K-Ras mutants. Multiple K-Ras inhibitors have the potential to address broad patient populations, including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant and K-Ras wild type amplified cancers.
  • Therefore, there are unmet needs to develop new multiple K-Ras inhibitors for treating K-Ras mediated cancers.
    • SUMMARY OF THE INVENTION
  • Provided herein is a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:
  • Figure US20240376128A1-20241114-C00002
  • Wherein, the definition of each of variables is as below.
  • Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof as defined herein; and a pharmaceutically acceptable excipient.
  • Also provided herein is a method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein to a subject in need thereof.
  • Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining whether the cancer is associated with K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification; and (b) if so, administering a therapeutically effective amount of a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein to the subject in need thereof.
  • Also provided herein is a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for use in therapy.
  • Also provided herein is a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for use as a medicament.
  • Also provided herein is a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for use in a method for the treatment of cancer.
  • Also provided herein is a use of a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for the treatment of cancer.
  • Also provided herein is a use of a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for the manufacture of a medicament for the treatment of cancer.
  • Also provided herein is a process for preparing a compound of Formula (IB) as defined herein.
  • Also provided herein is an intermediate for preparing a compound of Formula (IB) as defined herein.
    • DETAILED DESCRIPTION
  • Provided herein are the following disclosures:
  • [1]. A compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:
  • Figure US20240376128A1-20241114-C00003
    • Wherein,
      • R2a is selected from hydrogen, deuterium, —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, —N(Rb)2, —ORb, —SRb, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, —C2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —N(Rc)2, —OR, —SRc, —S(═O)Rd, —S(═O)2Ra, —C(═O)Rd, —C(═O)ORc, —OC(═O)Rd, —C(═O)N(Rc)2, —NRcC(═O)Rd, —OC(═O)ORc, —NRcC(═O)ORd, —OC(═O)N(Rc)2, —NRcC(═O)N(Rc)2, —S(═O)ORc, —OS(═O)Rd, —S(═O)N(Rc)2, —NRcS(═O)Rd, —S(═O)2ORc, —OS(═O)2Ra, —S(═O)2N(Rc)2, —NRcS(═O)2Ra, —OS(═O)2ORc, —NRcS(═O)2ORc, —OS(═O)2NRc, —NRcS(═O)2N(Rc)2, —P(Rc)2, —P(═O)(Rd)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • RS1 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R61)2, —OR61, —SR61, —S(═O)R62, —S(═O)2R62, —C(═O)R62, —C(═O)OR61, —OC(═O)R62, —C(═O)N(R61)2, —NR61C(═O)R62, —OC(═O)OR61, —NR61C(═O)OR61, —NR61C(═S)OR61, —OC(═O)N(R61)2, —NR61C(═O)N(R61)2, —S(═O)OR61, —OS(═O)R62, —S(═O)N(R61)2, —NR61S(═O)R62, —S(═O)2OR61, —OS(═O)2R62, —S(═O)2N(R61)2, —NR61S(═O)2R62, —OS(═O)2OR61, —NR61S(═O)2OR61, —OS(═O)2N(R61)2, —NR61S(═O)2N(R61)2, —P(R61)2, —P(═O)(R62)2,
  • Figure US20240376128A1-20241114-C00004
  • 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R63)2, —OR63, —SR63, —S(═O)R64, —S(═O)2R64, —C(═O)R64, —C(═O)OR64, —OC(═O)R64, —C(═O)N(R63)2, —NR63C(═O)R64, —OC(═O)OR63, —NR63C(═O)OR63, —NR63C(═S)OR63, —OC(═O)N(R63)2, —NR63C(═O)N(R63)2, —S(═O)OR63, —OS(═O)R64, —S(═O)N(R63)2, —NR63S(═O)R64, —S(═O)2OR63, —OS(═O)2R64, —S(═O)2N(R63)2, —NR63S(═O)2R64, —OS(═O)2OR63, —NR63S(═O)2OR63, —OS(═O)2N(R63)2, —NR63S(═O)2N(R63)2, —P(R63)2, —P(═O)(R64)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • Optionally, two RS1 together with the carbon atom to which they are both attached form
  • Figure US20240376128A1-20241114-C00005
      •  a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said
  • Figure US20240376128A1-20241114-C00006
      •  membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more R16c;
      • Optionally, two adjacent RS1 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R16d;
      • Optionally, two nonadjacent RS1 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S═O or S(═O)2; the hydrogen on the each of carbon atoms or N atoms is optionally independently substituted with R16e;
      • Y is a bond, O, S, S(═O), S(═O)2 or NR6a;
      • R2 is selected from -L5-(3-12 membered heterocyclyl), -L5-(3-12 membered cycloalkyl), -L5-(6-12 member aryl), -L5-(5-12 membered heteroaryl), -L5-N(R7a)2,
  • Figure US20240376128A1-20241114-C00007
      • Each of L5 at each occurrence is independently selected from a bond or C1-10 alkylene optionally substituted with one or more R16;
      • Said 3-12 membered heterocyclyl in -L5-(3-12 membered heterocyclyl) is optionally substituted with one or more R16o;
      • Said 3-12 membered cycloalkyl in -L5-(3-12 membered cycloalkyl) is optionally substituted with one or more R16o;
      • Said 6-12 member aryl in -L5-(6-12 member aryl) is optionally substituted with one or more R16o;
      • Said 5-12 membered heteroaryl in -L5-(5-12 membered heteroaryl) is optionally substituted with one or more R16o;
      • L6 is selected from a bond or C1-10 alkylene optionally substituted with one or more R16p;
      • L7 is selected from a bond or C1-10 alkylene optionally substituted with one or more R16q;
      • L8 is selected from a bond or C1-10 alkylene optionally substituted with one or more R16r;
      • Ring C or ring D is a 3-10 membered heterocyclic ring which is optionally further contains 1, 2, or 3 heteroatoms selected from N, O or S;
      • Ring E is selected from a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein the moiety of -L7- and -L8-X6 are attached to the same atom or different atoms of the ring E;
      • X6 is selected from —N(R65)2, —OR65, —SR65, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally independently substituted with one or more R16s;
      • Each of RS5 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R66)2, —OR66, —SR66, —S(═O)R6y, —S(═O)2R67, —C(═O)R6y, —C(═O)OR66, —OC(═O)R67, —C(═O)N(R66)2, —NR66C(═O)R6y, —OC(═O)OR66, —NR66C(═O)OR66, —NR66C(═S)OR66, —OC(═O)N(R66)2, —NR66C(═O)N(R66)2, —S(═O)OR66, —OS(═O)R6y, —S(═O)N(R66)2, —NR66S(═O)R66, —S(═O)2OR66, —OS(═O)2R67, —S(═O)2N(R66)2, —NR66S(═O)2R67, —OS(═O)2OR66, —NR66S(═O)2OR66, —OS(═O)2N(R66)2, —NR66S(═O)2N(R66)2, —P(R66)2, —P(═O)(R67)2,
  • Figure US20240376128A1-20241114-C00008
      •  3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R68)2, —OR68, —SR68, —S(═O)R69, —S(═O)2R69, —C(═O)R69, —C(═O)OR68, —OC(═O)R69, —C(═O)N(R68)2, —NR68C(═O)R69, —OC(═O)OR68, —NR68C(═O)OR68, —NR68C(═S)OR68, —OC(═O)N(R68)2, —NR68C(═O)N(R68)2, —S(═O)OR68, —OS(═O)R69, —S(═O)N(R68)2, —NR68S(═O)R69, —S(═O)2OR68, —OS(═O)2R69, —S(═O)2N(R68)2, —NR68S(═O)2R69, —OS(═O)2OR68, —NR68S(═O)2OR68, —OS(═O)2N(R68)2, —NR68S(═O)2N(R68)2, —P(R68)2, —P(═O)(R69)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • Optionally, two RS5 together with the carbon atom to which they are both attached form
  • Figure US20240376128A1-20241114-C00009
      •  a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 membered carbocyclic ring or 3-10 heterocyclic ring is optionally substituted with one or more R16t;
      • Optionally, two adjacent RS5 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R16u;
      • Optionally, two nonadjacent RS5 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S═O or S(═O)2; the hydrogen on the each of carbon atoms or N atoms is optionally independently substituted with R16v;
      • q5 is selected from 0, 1, 2, 3, 4, 5 or 6;
      • Each of RS6 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R71)2, —OR71, —SR71, —S(═O)R72, —S(═O)2R71, —C(═O)R72, —C(═O)OR71, —OC(═O)R72, —C(═O)N(R71)2, —NR71C(═O)R72, —OC(═O)OR71, —NR71C(═O)OR71, —OC(═O)N(R71)2, —NR71C(═O)N(R71)2, —S(═O)OR71, —OS(═O)R72, —S(═O)N(R71)2, —NR71S(═O)R72, —S(═O)2OR71, —OS(═O)2R72, —S(═O)2N(R71)2, —NR71S(═O)2R72, —OS(═O)2OR71, —NR71S(═O)2OR72, —OS(═O)2N(R71)2, —NR71S(═O)2N(R71)2, —P(R71)2, —P(═O)(R72)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R73)2, —OR73, —SR73, —S(═O)R74, —S(═O)2R73, —C(═O)R74, —C(═O)OR73, —OC(═O)R74, —C(═O)N(R73)2, —NR73C(═O)R74, —OC(═O)OR73, —NR73C(═O)OR73, —OC(═O)N(R73)2, —NR73C(═O)N(R73)2, —S(═O)OR73, —OS(═O)R74, —S(═O)N(R73)2, —NR73S(═O)R74, —S(═O)2OR73, —OS(═O)2R74, —S(═O)2N(R73)2, —NR73S(═O)2R74, —OS(═O)2OR73, —NR73S(═O)2OR74, —OS(═O)2N(R73)2, —NR73S(═O)2N(R73)2, —P(R73)2, —P(═O)(R74)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • q6 is selected from 0, 1, 2, 3, 4, 5 or 6;
      • R4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl
  • Figure US20240376128A1-20241114-C00010
      •  wherein said 6-10 membered aryl, 5-10 membered heteroaryl,
  • Figure US20240376128A1-20241114-C00011
      •  is optionally independently substituted with one or more R41;
      • Z at each occurrence is independently selected from C or N;
      • Ring G at each occurrence is independently selected from a 6 membered aryl ring or a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring when Z is selected from C;
      • Ring G at each occurrence is selected from a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered heterocyclic ring when Z is selected from N;
      • R41 at each occurrence is independently selected from deuterium, halogen, —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, —CN, —NO2, —N3, oxo, —N(R75)2, —OR75, —SR75, —S(═O)R76, —S(═O)2R76, —C(═O)R76, —C(═O)OR75, —OC(═O)R76, —C(═O)N(R75)2, —NR75C(═O)R76, —OC(═O)OR75, —NR75C(═O)OR75, —OC(═O)N(R75)2, —NR75C(═O)N(R75)2, —S(═O)OR75, —OS(═O)R76, —S(═O)N(R75)2, —NR75S(═O)R76, —S(═O)2OR75, —OS(═O)2R76, —S(═O)2N(R75)2, —NR75S(═O)2R76, —OS(═O)2OR75, —NR75S(═O)2OR75, —OS(═O)2N(R75)2, —NR75S(═O)2N(R75)2, —P(R75)2, —P(═O)(R75)2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R77)2, —OR77, —SR77, —S(═O)R78, —S(═O)2R78, —C(═O)R78, —C(═O)OR77, —OC(═O)R78, —C(═O)N(R77)2, —NR77C(═O)R78, —OC(═O)OR77, —NR77C(═O)OR77, —OC(═O)N(R77)2, —NR77C(═O)N(R77)2, —S(═O)OR77, —OS(═O)Rys, —S(═O)N(R77)2, —NR77S(═O)R78, —S(═O)2OR77, —OS(═O)2R78, —S(═O)2N(R77)2, —NR77S(═O)2R78, —OS(═O)2OR77, —NR77S(═O)2OR77, —OS(═O)2N(R77)2, —NR77S(═O)2N(R77)2, —P(R77)2, —P(═O)(R78)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • Each of (R51 and R52) is independently selected from hydrogen, deuterium, halogen, —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, —CN, —NO2, —N3, oxo, —N(R81)2, —OR81, —SR1, —S(═O)R82, —S(═O)2R82, —C(═O)R82, —C(═O)OR81, —OC(═O)R82, —C(═O)N(R81)2, —NR81C(═O)R82, —OC(═O)OR81, —NR81C(═O)OR81, —OC(═O)N(R %1)2, —NR81C(═O)N(R81)2, —S(═O)OR81, —OS(═O)R82, —S(═O)N(R81)2, —NR81S(═O)R82, —S(═O)2OR81, —OS(═O)2R82, —S(═O)2N(R81)2, —NR81S(═O)2R82, —OS(═O)2OR81, —NR81S(═O)2OR81, —OS(═O)2N(R81)2, —NR81S(═O)2N(R81)2, —P(R81)2, —P(═O)(R82)2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R83)2, —OR83, —SR83, —S(═O)R84, —S(═O)2R84, —C(═O)R84, —C(═O)OR83, —OC(═O)R83, —C(═O)N(R83)2, —NR83C(═O)R84, —OC(═O)OR83, —NR83C(═O)OR83, —OC(═O)N(R83)2, —NR83C(═O)N(R84)2, —S(═O)OR83, —OS(═O)R84, —S(═O)N(R83)2, —NR83S(═O)R %4, —S(═O)2OR83, —OS(═O)2R84, —S(═O)2N(R83)2, —NR83S(═O)2R84, —OS(═O)2OR83, —NR83S(═O)2OR83, —OS(═O)2N(R83)2, —NR83S(═O)2N(R83)2, —P(R83)2, —P(═O)(R84)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • Each of (R6a, R7a, R61, R63, R65, R66, R68, R71, R73, R75, R77, R81 and R83) at each occurrence is independently selected from hydrogen, deuterium, halogen, —C1-10alkyl, haloC1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —S(═O)Ra, —S(═O)2Ra, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Ra)2, —S(═O)ORa, —S(═O)N(Ra)2, —S(═O)2ORa, —S(═O)2N(Ra)2, —P(═O)(Ra)2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-10alkyl, haloC1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —N(Rc)2, —ORc, —SRc, —S(═O)Rd, —S(═O)2Rd, —C(═O)Rd, —C(═O)OR, —OC(═O)Rd, —C(═O)N(R)2, —NRC(═O)Ra, —OC(═O)OR, —NRC(═O)ORa, —OC(═O)N(R)2, —NRC(═O)N(Rc)2, —S(═O)ORc, —OS(═O)Rd, —S(═O)N(R)2, —NRS(═O)Ra, —S(═O)2OR, —OS(═O)2Rd, —S(═O)2N(R)2, —NRS(═O)2Rd, —OS(═O)2OR, —NRS(═O)2OR, —OS(═O)2NR, —NRS(═O)2N(R)2, —P(Rc)2, —P(═O)(Ra)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • Optionally, each of (two R7a, two R61, two R63, two R65, two R66, two R68, two R71, two R73, two R75, two R77, two R81, and two R83) independently together with the nitrogen atom to which they are both attached forms a 3-20 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein, said 3-20 membered heterocyclic ring or 5-10 membered heteroaryl ring is optionally independently substituted with one or more R16W;
      • Each of (R62, R64, R67, R69, R72, R74, R76, R78, R82 and R84) at each occurrence is independently selected from hydrogen, deuterium, —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, —N(Rb)2, —ORb, —SRb, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, —C2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —N(Rc)2, —OR, —SR, —S(═O)Ra, —S(═O)2Ra, —C(═O)Ra, —C(═O)OR, —OC(═O)Rd, —C(═O)N(R)2, —NRC(═O)Ra, —OC(═O)OR, —NRC(═O)ORa, —OC(═O)N(R)2, —NRC(═O)N(R)2, —S(═O)OR, —OS(═O)Rd, —S(═O)N(R)2, —NRS(═O)Ra, —S(═O)2OR, —OS(═O)2Rd, —S(═O)2N(R)2, —NRS(═O)2Rd, —OS(═O)2OR, —NRS(═O)2OR, —OS(═O)2NR, —NRS(═O)2N(Rc)2, —P(Rc)2, —P(═O)(Rd)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • Each of (Ra, Rb, Rc and Rd) at each occurrence is independently selected from hydrogen, deuterium, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more R16x;
      • Optionally, each of (two Ra, two Rb and two Rc) independently together with the atom to which they are both attached forms a 3-6 membered heterocyclic ring, wherein said 3-6 membered heterocyclic ring is independently optionally substituted with one or more R16y;
      • Each of (R16c, R16d, R16e, R16n, R16o, R16p, R16q, R16r, R16s, R16t, R16u, R16v, R16w, R16x and R16y) at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —OC(═O)O(C1-6alkyl), —NHC(═O)(OC1-6alkyl), —N(C1-6alkyl)C(═O)(OC1-6alkyl), —OC(═O)NH(C1-6alkyl), —OC(═O)N(C1-6alkyl)2, —NHC(═O)NH2, —NHC(═O)NH(C1-6alkyl), —NHC(═O)N(C1-6alkyl)2, —N(C1-6alkyl)C(═O)NH2, —N(C1-6alkyl)C(═O)NH(C1-6alkyl), —N(C1-6alkyl)C(═O)N(C1-6alkyl)2, —S(═O)(OC1-6alkyl), —OS(═O)(C1-6alkyl), —S(═O)NH2, —S(═O)NH(C1-6alkyl), —S(═O)N(C1-6alkyl)2, —NHS(═O)(C1-6alkyl), —N(C1-6alkyl)S(═O)(C1-6alkyl), —S(═O)2(OC1-6alkyl), —OS(═O)2(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), —OS(═O)2O(C1-6alkyl), —NHS(═O)2O(C1-6alkyl), —N(C1-6alkyl)S(═O)2O(C1-6alkyl), —OS(═O)2NH2, —OS(═O)2NH(C1-6alkyl), —OS(═O)2N(C1-6alkyl)2, —NHS(═O)2NH2, —NHS(═O)2NH(C1-6alkyl), —NHS(═O)2N(C1-6alkyl)2, —N(C1-6alkyl)S(═O)2NH2, —N(C1-6alkyl)S(═O)2NH(C1-6alkyl), —N(C1-6alkyl)S(═O)2N(C1-6alkyl)2, —PH(C1-6alkyl), —P(C1-6alkyl)2, —P(═O)H(C1-6alkyl), —P(═O)(C1-6alkyl)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —C2-3alkenyl, —C2-3alkynyl, —CN, —NO2, —N3, oxo, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —O(C1-3alkyl), —SH, —S(C1-3alkyl), —S(═O)(C1-3alkyl), —S(═O)2(C1-3alkyl), —C(═O)(C1-3alkyl), —C(═O)OH, —C(═O)(OC1-3alkyl), —OC(═O)(C1-3alkyl), —C(═O)NH2, —C(═O)NH(C1-3alkyl), —C(═O)N(C1-3alkyl)2, —NHC(═O)(C1-3alkyl), —N(C1-3alkyl)C(═O)(C1-3alkyl), —OC(═O)O(C1-3alkyl), —NHC(═O)(OC1-3alkyl), —N(C1-3alkyl)C(═O)(OC1-3alkyl), —OC(═O)NH(C1-3alkyl), —OC(═O)N(C1-3alkyl)2, —NHC(═O)NH2, —NHC(═O)NH(C1-3alkyl), —NHC(═O)N(C1-3alkyl)2, —N(C1-3alkyl)C(═O)NH2, —N(C1-3alkyl)C(═O)NH(C1-3alkyl), —N(C1-3alkyl)C(═O)N(C1-3alkyl)2, —S(═O)(OC1-3alkyl), —OS(═O)(C1-3alkyl), —S(═O)NH2, —S(═O)NH(C1-3alkyl), —S(═O)N(C1-3alkyl)2, —NHS(═O)(C1-3alkyl), —N(C1-3alkyl)S(═O)(C1-3alkyl), —S(═O)2(OC1-3alkyl), —OS(═O)2(C1-3alkyl), —S(═O)2NH2, —S(═O)2NH(C1-3alkyl), —S(═O)2N(C1-3alkyl)2, —NHS(═O)2(C1-3alkyl), —N(C1-3alkyl)S(═O)2(C1-3alkyl), —OS(═O)2O(C1-3alkyl), —NHS(═O)2O(C1-3alkyl), —N(C1-3alkyl)S(═O)2O(C1-3alkyl), —OS(═O)2NH2, —OS(═O)2NH(C1-3alkyl), —OS(═O)2N(C1-3alkyl)2, —NHS(═O)2NH2, —NHS(═O)2NH(C1-3alkyl), —NHS(═O)2N(C1-3alkyl)2, —N(C1-3alkyl)S(═O)2NH2, —N(C1-3alkyl)S(═O)2NH(C1-3alkyl), —N(C1-3alkyl)S(═O)2N(C1-3alkyl)2, —PH(C1-3alkyl), —P(C1-3alkyl)2, —P(═O)H(C1-3alkyl), —P(═O)(C1-3alkyl)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6 membered aryl or 5-6 membered heteroaryl;
      • Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(═O) or S(═O)2.
  • [2]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of [1], wherein, the compound is selected from any one of the following formulas:
  • Figure US20240376128A1-20241114-C00012
      • Wherein:
      • RS1 linked with the carbon atom indicated with ** and NR2a linked with the carbon atom indicated with * are in a trans configuration;
      • RS1 linked with the carbon atom indicated with ## and NR2a linked with the carbon atom indicated with # are in a cis configuration.
  • [3]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of [1] or [2], wherein, R2a is selected from hydrogen, deuterium, —C1-6alkyl, haloC1-6alkyl, —C1-6alkoxy, —C(═O)C1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2, phenyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; wherein said —C1-6alkyl, haloC1-6alkyl, —C1-6alkoxy, —C(═O)C1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-3alkyl, haloC1-3alkyl, —C2-3alkenyl, —C2-3alkynyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2, phenyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S.
  • [4]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [3], wherein, R2a is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, iso-hexyl, sec-hexyl, tert-hexyl, halomethyl, haloethyl, methoxy, ethoxy, —C(═O)CH3, —C(═O)CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyryl, phenyl, thiophenyl or pyridinyl, wherein, said methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, iso-hexyl, sec-hexyl, tert-hexyl, halomethyl, haloethyl, methoxy, ethoxy, —C(═O)CH3, —C(═O)CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyryl, phenyl, thiophenyl or pyridinyl is optionally independently substituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, —F, methyl, ethyl, propyl, isopropyl, —CH2F, —CHF2, —CF3, —CN, —NH2, —NHCH3, —N(CH3)2, —OH, —OCH3, —SH, —SCH3, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)OCH2CH3, —OC(═O)CH3, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • [5]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [4], wherein, R2a is selected from any moiety in the Table 1:
  • TABLE 1
    —H,
    —CH3,
    —CD3,
    —OCH3,
    —CH2CN,
    —CH2CH3,
    —CH2CH2F,
    —CH2CHF2,
    —CH2CH2OCH3,
    —C(═O)CH3,
    —CH2C(═O)OCH2CH3,
    Figure US20240376128A1-20241114-C00013
    Figure US20240376128A1-20241114-C00014
    Figure US20240376128A1-20241114-C00015
    Figure US20240376128A1-20241114-C00016
    Figure US20240376128A1-20241114-C00017
    Figure US20240376128A1-20241114-C00018
    Figure US20240376128A1-20241114-C00019
    Figure US20240376128A1-20241114-C00020
    Figure US20240376128A1-20241114-C00021
    Figure US20240376128A1-20241114-C00022
    Figure US20240376128A1-20241114-C00023
    Figure US20240376128A1-20241114-C00024
    Figure US20240376128A1-20241114-C00025
    Figure US20240376128A1-20241114-C00026
    Figure US20240376128A1-20241114-C00027
    Figure US20240376128A1-20241114-C00028
    Figure US20240376128A1-20241114-C00029
    Figure US20240376128A1-20241114-C00030
    Figure US20240376128A1-20241114-C00031
    Figure US20240376128A1-20241114-C00032
    Figure US20240376128A1-20241114-C00033
    Figure US20240376128A1-20241114-C00034
    or
    Figure US20240376128A1-20241114-C00035
  • [6]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [5], wherein, RS1 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
      • Optionally, two RS1 together with the carbon atom to which they are both attached form
  • Figure US20240376128A1-20241114-C00036
      •  a 3-6 membered carbocyclic ring or a 3-6 heterocyclic ring; wherein, said
  • Figure US20240376128A1-20241114-C00037
  • 3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more substitutents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
      • Optionally, two adjacent RS1 together with the carbon atoms to which they are respectively attached form a 3-6 membered carbocyclic ring, or a 3-6 membered heterocyclic ring, wherein, each of rings is independently optionally substituted with one or more substitutents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl.
  • [7]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [6], wherein, RS1 at each occurrence is independently selected from deuterium, —F, —Cl, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, iso-hexyl, sec-hexyl, tert-hexyl, halomethyl, haloethyl, —CN, —NH2, —NHCH3, —N(CH3)2, —OH, methoxy, ethoxy, —SH, —SCH3, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3 or —OC(═O)CH3; wherein said methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, iso-hexyl, sec-hexyl, tert-hexyl, halomethyl, haloethyl, methoxy, ethoxy is optionally independently substituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, —F, methyl, ethyl, propyl, isopropyl, —CH2F, —CHF2, —CF3, —CN, —NH2, —NHCH3, —N(CH3)2, —OH, —OCH3, —SH, —SCH3, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)OCH2CH3 or —OC(═O)CH3;
      • Optionally two RS1 together with the carbon atom to which they are both attached form
  • Figure US20240376128A1-20241114-C00038
      •  wherein, said
  • Figure US20240376128A1-20241114-C00039
      •  is optionally substituted with one or more substituents selected from deuterium, —F, —Cl, methyl, ethyl, propyl, isopropyl, —CH2F, —CHF2 or —CF3.
  • [8]. The compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof of any one of [1] to [7], wherein, RS1 at each occurrence is independently selected from -D, —F, —CH3, —CD3, —CH2F, —CHF2, —CF3, —CN, —CH2CN, —OH, —OCH3, —OCD3, —NHCH3, —SCH3, —CH2OCH3, —C(═O)CH3, —CH2CH3, —CHFCF3,
  • Figure US20240376128A1-20241114-C00040
  • [9]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [8], wherein, the moiety of
  • Figure US20240376128A1-20241114-C00041
  • is selected from the moiety in the Table 2:
  • TABLE 2
    Figure US20240376128A1-20241114-C00042
    Figure US20240376128A1-20241114-C00043
    Figure US20240376128A1-20241114-C00044
    Figure US20240376128A1-20241114-C00045
    Figure US20240376128A1-20241114-C00046
    Figure US20240376128A1-20241114-C00047
    Figure US20240376128A1-20241114-C00048
    Figure US20240376128A1-20241114-C00049
    Figure US20240376128A1-20241114-C00050
    Figure US20240376128A1-20241114-C00051
    Figure US20240376128A1-20241114-C00052
    Figure US20240376128A1-20241114-C00053
    Figure US20240376128A1-20241114-C00054
    Figure US20240376128A1-20241114-C00055
    Figure US20240376128A1-20241114-C00056
    Figure US20240376128A1-20241114-C00057
    Figure US20240376128A1-20241114-C00058
    Figure US20240376128A1-20241114-C00059
    Figure US20240376128A1-20241114-C00060
    Figure US20240376128A1-20241114-C00061
    Figure US20240376128A1-20241114-C00062
    Figure US20240376128A1-20241114-C00063
    Figure US20240376128A1-20241114-C00064
    Figure US20240376128A1-20241114-C00065
    Figure US20240376128A1-20241114-C00066
    Figure US20240376128A1-20241114-C00067
    Figure US20240376128A1-20241114-C00068
    Figure US20240376128A1-20241114-C00069
    Figure US20240376128A1-20241114-C00070
    Figure US20240376128A1-20241114-C00071
    Figure US20240376128A1-20241114-C00072
    Figure US20240376128A1-20241114-C00073
    Figure US20240376128A1-20241114-C00074
    Figure US20240376128A1-20241114-C00075
    Figure US20240376128A1-20241114-C00076
    Figure US20240376128A1-20241114-C00077
    Figure US20240376128A1-20241114-C00078
    Figure US20240376128A1-20241114-C00079
    Figure US20240376128A1-20241114-C00080
    Figure US20240376128A1-20241114-C00081
    Figure US20240376128A1-20241114-C00082
    Figure US20240376128A1-20241114-C00083
    Figure US20240376128A1-20241114-C00084
    Figure US20240376128A1-20241114-C00085
    Figure US20240376128A1-20241114-C00086
    Figure US20240376128A1-20241114-C00087
    Figure US20240376128A1-20241114-C00088
    Figure US20240376128A1-20241114-C00089
    Figure US20240376128A1-20241114-C00090
    Figure US20240376128A1-20241114-C00091
    Figure US20240376128A1-20241114-C00092
    Figure US20240376128A1-20241114-C00093
    Figure US20240376128A1-20241114-C00094
    Figure US20240376128A1-20241114-C00095
    Figure US20240376128A1-20241114-C00096
    Figure US20240376128A1-20241114-C00097
    Figure US20240376128A1-20241114-C00098
    Figure US20240376128A1-20241114-C00099
    Figure US20240376128A1-20241114-C00100
    Figure US20240376128A1-20241114-C00101
    Figure US20240376128A1-20241114-C00102
    Figure US20240376128A1-20241114-C00103
    Figure US20240376128A1-20241114-C00104
    Figure US20240376128A1-20241114-C00105
    Figure US20240376128A1-20241114-C00106
    Figure US20240376128A1-20241114-C00107
    Figure US20240376128A1-20241114-C00108
    Figure US20240376128A1-20241114-C00109
    Figure US20240376128A1-20241114-C00110
    Figure US20240376128A1-20241114-C00111
    Figure US20240376128A1-20241114-C00112
    Figure US20240376128A1-20241114-C00113
    Figure US20240376128A1-20241114-C00114
    Figure US20240376128A1-20241114-C00115
    Figure US20240376128A1-20241114-C00116
    Figure US20240376128A1-20241114-C00117
    Figure US20240376128A1-20241114-C00118
    Figure US20240376128A1-20241114-C00119
    Figure US20240376128A1-20241114-C00120
    Figure US20240376128A1-20241114-C00121
    Figure US20240376128A1-20241114-C00122
    Figure US20240376128A1-20241114-C00123
    Figure US20240376128A1-20241114-C00124
    Figure US20240376128A1-20241114-C00125
    Figure US20240376128A1-20241114-C00126
    Figure US20240376128A1-20241114-C00127
    Figure US20240376128A1-20241114-C00128
    Figure US20240376128A1-20241114-C00129
    Figure US20240376128A1-20241114-C00130
    Figure US20240376128A1-20241114-C00131
    Figure US20240376128A1-20241114-C00132
    Figure US20240376128A1-20241114-C00133
    Figure US20240376128A1-20241114-C00134
    Figure US20240376128A1-20241114-C00135
    Figure US20240376128A1-20241114-C00136
    Figure US20240376128A1-20241114-C00137
    Figure US20240376128A1-20241114-C00138
    Figure US20240376128A1-20241114-C00139
    Figure US20240376128A1-20241114-C00140
    Figure US20240376128A1-20241114-C00141
    Figure US20240376128A1-20241114-C00142
    Figure US20240376128A1-20241114-C00143
    Figure US20240376128A1-20241114-C00144
    Figure US20240376128A1-20241114-C00145
    Figure US20240376128A1-20241114-C00146
    Figure US20240376128A1-20241114-C00147
    Figure US20240376128A1-20241114-C00148
    or
    Figure US20240376128A1-20241114-C00149
  • [10]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [2] to [9], wherein, the moiety of
  • Figure US20240376128A1-20241114-C00150
  • is selected from the moiety in the Table 3:
  • TABLE 3
    Figure US20240376128A1-20241114-C00151
    Figure US20240376128A1-20241114-C00152
    Figure US20240376128A1-20241114-C00153
    Figure US20240376128A1-20241114-C00154
    Figure US20240376128A1-20241114-C00155
    Figure US20240376128A1-20241114-C00156
    Figure US20240376128A1-20241114-C00157
    Figure US20240376128A1-20241114-C00158
    Figure US20240376128A1-20241114-C00159
    Figure US20240376128A1-20241114-C00160
    Figure US20240376128A1-20241114-C00161
    Figure US20240376128A1-20241114-C00162
    Figure US20240376128A1-20241114-C00163
    Figure US20240376128A1-20241114-C00164
    Figure US20240376128A1-20241114-C00165
    Figure US20240376128A1-20241114-C00166
    Figure US20240376128A1-20241114-C00167
    Figure US20240376128A1-20241114-C00168
    Figure US20240376128A1-20241114-C00169
    Figure US20240376128A1-20241114-C00170
    or
    Figure US20240376128A1-20241114-C00171
  • [11]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [10], wherein, the compound is selected from any one of the following formulas:
  • Figure US20240376128A1-20241114-C00172
    Figure US20240376128A1-20241114-C00173
    Figure US20240376128A1-20241114-C00174
    Figure US20240376128A1-20241114-C00175
    Figure US20240376128A1-20241114-C00176
    Figure US20240376128A1-20241114-C00177
      • Wherein, R2a is selected from hydrogen, deuterium, —C1-6alkyl, haloC1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, or 5-6 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-3alkyl, haloC1-3alkyl, —C2-3alkenyl, —C2-3alkynyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
      • RS1 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
      • Optionally, two RS1 together with the carbon atom to which they are both attached form
  • Figure US20240376128A1-20241114-C00178
      •  a 3-6 membered carbocyclic ring or a 3-6 heterocyclic ring; wherein, said
  • Figure US20240376128A1-20241114-C00179
      •  3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more substitutents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
      • Optionally, two adjacent RS1 together with the carbon atoms to which they are respectively attached form a 3-6 membered carbocyclic ring, or a 3-6 membered heterocyclic ring, wherein, each of rings is independently optionally substituted with one or more substitutents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl.
  • RS1 linked with the carbon atom indicated with ** and NR2a linked with the carbon atom indicated with * are in a trans configuration;
      • RS1 linked with the carbon atom indicated with ## and NR2a linked with the carbon atom indicated with # are in a cis configuration;
      • p is selected from 0, 1, 2 or 3.
  • [12]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [11], wherein, RS5 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-3alkenyl, —CN, —N(R66)2, —OR66, —SR66, —C(═O)R67, —C(═O)OR66, —OC(═O)R67, —C(═O)N(R66)2, —NR66C(═O)R67, —OC(═O)OR66, —NR66C(═O)OR66, —OC(═O)N(R66)2, —NR66C(═O)N(R66)2, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S or
  • Figure US20240376128A1-20241114-C00180
  • wherein, said —C1-6alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —CN, oxo, —N(R68)2, —OR68, —C(═O)R68, —C(═O)OR68, —OC(═O)R68, —C(—)NR68)2, —NR68C(═O)R69, —OC(═O)OR68, —NR68C(═O)OR69, —OC(═O)N(R68)2, —OC(═S)N(R68)2, —NR68C(═O)N(R68)2, —NR68S(═O)2R69, 3-6 membered cycloalkyl or 4-6 membered heterocyclyl; said 4-8 membered heterocyclyl is substituted with 1, 2 or 3 substituents selected from deuterium or —OR68; said haloC1-6alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, —OR68 or —C(═O)OR68; said —C2-3alkenyl is substituted with 1 substituents selected from deuterium or —C(═O)NR68R69;
      • Optionally, two R85 together with the carbon atom to which they are both attached form
  • Figure US20240376128A1-20241114-C00181
      • Each of (R66 or R67) is independently selected from hydrogen; deuterium; —C1-6alkyl; haloC1-6alkyl; or —C1-6alkyl substituted with 1 or 2 substituents selected from —C(═O)N(C1-6alkyl)2, —OC1-6alkyl, —C(═O)OC1-6alkyl, —NHC1-6alkyl or —N(C1-6alkyl)2;
      • Each of (R68 or R69) is independently selected from hydrogen; deuterium; —C1-6alkyl; haloC1-6alkyl; 5 membered heteroaryl; cyclopropyl; cyclopentyl; cyclohexyl; 5 membered heterocyclyl; 6 membered heterocyclyl; 5-membered heteroaryl; 6 membered heteroaryl; or —C1-6alkyl substituted with 1, or 2 substituents selected from deuterium, —OC1-6alkyl, —NHC1-6alkyl, —N(C1-6alkyl)2 or —C(═O)N(C1-6alkyl)2; wherein said 5 membered heteroaryl, cyclopropyl, cyclopentyl, cyclohexyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5-membered heteroaryl or 6 membered heteroaryl is optionally substituted with 1 or 2 substitutents selected from deuterium, —C1-3alkyl, —OH, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OC1-3alkyl or cyclopropyl;
      • Optionally, two R66 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring;
      • Optionally, two R68 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring.
  • [13]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [12], wherein, RS5 at each occurrence is independently selected from deuterium, —F, —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —N(R66)2, —OR66, —SR66, —C(═O)R67, —C(═O)OR66, —OC(═O)R67, —C(═O)N(R66)2, —NR66C(═O)R67, —OC(═O)OR66, —NR66C(═O)OR66, —OC(═O)N(R66)2 or —NR66C(═O)N(R66)2; wherein, said —C1-3alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, halogen, —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —CN, oxo, —N(R68)2, —OR68, —C(═O)R68, —C(═O)OR68, —OC(═O)R68, —C(═O)N(R68)2, —NR68C(═O)R69, —OC(═O)OR68, —NR68C(═O)OR69, —OC(═O)N(R68)2, —OC(═S)N(R68)2, —NR68C(═O)N(R68)2 or —NR68S(═O)2R69;
      • Optionally, two RS5 together with the carbon atom to which they are both attached form
  • Figure US20240376128A1-20241114-C00182
  • said
  • Figure US20240376128A1-20241114-C00183
  • is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, —F, —C1-3alkyl or haloC1-3alkyl;
      • R66 or R68 at each occurrence is independently selected from hydrogen, deuterium or —C1-3alkyl;
      • Optionally, two R66 together with the nitrogen atom to which they are both attached forms a 3-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2;
      • Optionally, two R68 together with the nitrogen atom to which they are both attached forms a 3-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2;
      • R67 or R69 at each occurrence is independently selected from hydrogen, deuterium or —C1-3alkyl.
  • [14]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [13], wherein, RS5 at each occurrence is independently selected from deuterium, —F, —Cl, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH═CH2, —C≡CH, —C≡CCH3, —C≡CD, —CH2C≡CH, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CH2CH2CH2F, —OH, —CH2OH, —CH2CH2OH, —OCH3, —OC(CH3)2, —OCH2CH3, —OCH(CH3)2, —OCF3, —SH, —SCH3, —SCF3, —C(═O)CF3, —CN, —NH2, —N(CH3)2, —NHCH2CH3, —CH2N(CH3)2, —NHC(═O)CH3, —NHC(═O)OCH3, —CH2NHC(═O)OCH3, —OC(═O)NHCH3, —OC(═O)N(CH3)2, —CH2OC(═O)N(CH3)2, —CH2OC(═O)NHCH3, —NHC(═O)N(CH3)2, —CH2NHC(═O)N(CH3)2, —CH2NHC(═O)CH3, —CH2OCH3, or
  • Figure US20240376128A1-20241114-C00184
  • [15]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [14], wherein, q5 is selected from 0, 1 or
  • [16]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [15], wherein, q5 is selected from 0 or 1.
  • [17]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of am one of [1] to [16], wherein, the moiety of
  • Figure US20240376128A1-20241114-C00185
  • is selected from any moiety in the Table 4:
  • TABLE 4
    Figure US20240376128A1-20241114-C00186
    Figure US20240376128A1-20241114-C00187
    Figure US20240376128A1-20241114-C00188
    Figure US20240376128A1-20241114-C00189
    Figure US20240376128A1-20241114-C00190
    Figure US20240376128A1-20241114-C00191
    Figure US20240376128A1-20241114-C00192
    Figure US20240376128A1-20241114-C00193
    Figure US20240376128A1-20241114-C00194
    Figure US20240376128A1-20241114-C00195
    Figure US20240376128A1-20241114-C00196
    Figure US20240376128A1-20241114-C00197
    Figure US20240376128A1-20241114-C00198
    Figure US20240376128A1-20241114-C00199
    Figure US20240376128A1-20241114-C00200
    Figure US20240376128A1-20241114-C00201
    Figure US20240376128A1-20241114-C00202
    Figure US20240376128A1-20241114-C00203
    Figure US20240376128A1-20241114-C00204
    Figure US20240376128A1-20241114-C00205
    Figure US20240376128A1-20241114-C00206
    Figure US20240376128A1-20241114-C00207
    Figure US20240376128A1-20241114-C00208
    Figure US20240376128A1-20241114-C00209
    Figure US20240376128A1-20241114-C00210
    Figure US20240376128A1-20241114-C00211
    Figure US20240376128A1-20241114-C00212
    Figure US20240376128A1-20241114-C00213
    Figure US20240376128A1-20241114-C00214
    Figure US20240376128A1-20241114-C00215
    Figure US20240376128A1-20241114-C00216
    Figure US20240376128A1-20241114-C00217
    Figure US20240376128A1-20241114-C00218
    Figure US20240376128A1-20241114-C00219
    Figure US20240376128A1-20241114-C00220
    Figure US20240376128A1-20241114-C00221
    Figure US20240376128A1-20241114-C00222
    Figure US20240376128A1-20241114-C00223
    Figure US20240376128A1-20241114-C00224
    Figure US20240376128A1-20241114-C00225
    or
    Figure US20240376128A1-20241114-C00226
  • [18]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [11] to [17], wherein, the moiety of
  • Figure US20240376128A1-20241114-C00227
  • is selected from any moiety in the Table 5:
  • TABLE 5
    Figure US20240376128A1-20241114-C00228
    Figure US20240376128A1-20241114-C00229
    Figure US20240376128A1-20241114-C00230
    Figure US20240376128A1-20241114-C00231
    Figure US20240376128A1-20241114-C00232
    Figure US20240376128A1-20241114-C00233
    Figure US20240376128A1-20241114-C00234
    Figure US20240376128A1-20241114-C00235
    Figure US20240376128A1-20241114-C00236
    Figure US20240376128A1-20241114-C00237
    Figure US20240376128A1-20241114-C00238
    Figure US20240376128A1-20241114-C00239
    Figure US20240376128A1-20241114-C00240
    or
    Figure US20240376128A1-20241114-C00241

    [19]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [8] wherein, R4 is selected from any moiety in the Table 6:
  • TABLE 6
    Figure US20240376128A1-20241114-C00242
    Figure US20240376128A1-20241114-C00243
    Figure US20240376128A1-20241114-C00244
    Figure US20240376128A1-20241114-C00245
    Figure US20240376128A1-20241114-C00246
    Figure US20240376128A1-20241114-C00247
    Figure US20240376128A1-20241114-C00248
    Figure US20240376128A1-20241114-C00249
    Figure US20240376128A1-20241114-C00250
    Figure US20240376128A1-20241114-C00251
    Figure US20240376128A1-20241114-C00252
    Figure US20240376128A1-20241114-C00253
    Figure US20240376128A1-20241114-C00254
    Figure US20240376128A1-20241114-C00255
    Figure US20240376128A1-20241114-C00256
    Figure US20240376128A1-20241114-C00257
    Figure US20240376128A1-20241114-C00258
    Figure US20240376128A1-20241114-C00259
    Figure US20240376128A1-20241114-C00260
    Figure US20240376128A1-20241114-C00261
    Figure US20240376128A1-20241114-C00262
    Figure US20240376128A1-20241114-C00263
    Figure US20240376128A1-20241114-C00264
    Figure US20240376128A1-20241114-C00265
    Figure US20240376128A1-20241114-C00266
    Figure US20240376128A1-20241114-C00267
    Figure US20240376128A1-20241114-C00268
    Figure US20240376128A1-20241114-C00269
    Figure US20240376128A1-20241114-C00270
    Figure US20240376128A1-20241114-C00271
    Figure US20240376128A1-20241114-C00272
    Figure US20240376128A1-20241114-C00273
    Figure US20240376128A1-20241114-C00274
    Figure US20240376128A1-20241114-C00275
    Figure US20240376128A1-20241114-C00276
    Figure US20240376128A1-20241114-C00277
    Figure US20240376128A1-20241114-C00278
    Figure US20240376128A1-20241114-C00279
    Figure US20240376128A1-20241114-C00280
    Figure US20240376128A1-20241114-C00281
    Figure US20240376128A1-20241114-C00282
    Figure US20240376128A1-20241114-C00283
    Figure US20240376128A1-20241114-C00284
    Figure US20240376128A1-20241114-C00285
    Figure US20240376128A1-20241114-C00286
    Figure US20240376128A1-20241114-C00287
    Figure US20240376128A1-20241114-C00288
    Figure US20240376128A1-20241114-C00289
    Figure US20240376128A1-20241114-C00290
    Figure US20240376128A1-20241114-C00291
    Figure US20240376128A1-20241114-C00292
    Figure US20240376128A1-20241114-C00293
    Figure US20240376128A1-20241114-C00294
    Figure US20240376128A1-20241114-C00295
    Figure US20240376128A1-20241114-C00296
    Figure US20240376128A1-20241114-C00297
    or
    Figure US20240376128A1-20241114-C00298
  • Wherein, each moiety in the Table 6 is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R41.
  • [20]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [19], wherein, the compound is selected from any one of the following formulas:
  • Figure US20240376128A1-20241114-C00299
    Figure US20240376128A1-20241114-C00300
    Figure US20240376128A1-20241114-C00301
    Figure US20240376128A1-20241114-C00302
      • R16 is selected from hydrogen or deuterium;
      • s is selected from 0, 1, 2, 3, 4, 5 or 6;
      • t is selected from 0, 1, 2, 3 or 4;
      • RS1 linked with the carbon atom indicated with ** and NR2a linked with the carbon atom indicated with * are in a trans configuration;
      • RS1 linked with the carbon atom indicated with ## and NR2a linked with the carbon atom indicated with # are in a cis configuration.
  • [21]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [20], wherein, R41 is independently selected from —F, —Cl, —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —C2-3alkenyl, —C2-3alkynyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —O(C1-3alkyl), —SH, —S(C1-3alkyl), —S(═O)H, —S(═O)(C1-3alkyl), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein said —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —C2-3alkenyl, —C2-6alkynyl, —NH2, —SH, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is independently optionally substituted with 1, 2 or 3 R42;
      • Each of R42 is independently selected from —F; —C1-3alkyl; haloC1-3alkyl; —CN; —OH; —NH2; —NH(C1-3alkyl); —N(C1-3alkyl)2; —OC1-3alkyl; 3-6 membered cycloalkyl; or —C1-3alkyl substituted with 1, 2 or 3 substituents selected from —F, haloC1-3alkyl, —CN, —OH, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2 or —OC1-3alkyl.
  • [22]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [21], wherein, R4 is selected from any moiety in the Table 7:
  • TABLE 7
    Figure US20240376128A1-20241114-C00303
    Figure US20240376128A1-20241114-C00304
    Figure US20240376128A1-20241114-C00305
    Figure US20240376128A1-20241114-C00306
    Figure US20240376128A1-20241114-C00307
    Figure US20240376128A1-20241114-C00308
    Figure US20240376128A1-20241114-C00309
    Figure US20240376128A1-20241114-C00310
    Figure US20240376128A1-20241114-C00311
    Figure US20240376128A1-20241114-C00312
    Figure US20240376128A1-20241114-C00313
    Figure US20240376128A1-20241114-C00314
    Figure US20240376128A1-20241114-C00315
    Figure US20240376128A1-20241114-C00316
    Figure US20240376128A1-20241114-C00317
    Figure US20240376128A1-20241114-C00318
    Figure US20240376128A1-20241114-C00319
    Figure US20240376128A1-20241114-C00320
    Figure US20240376128A1-20241114-C00321
    Figure US20240376128A1-20241114-C00322
    Figure US20240376128A1-20241114-C00323
    Figure US20240376128A1-20241114-C00324
    Figure US20240376128A1-20241114-C00325
    Figure US20240376128A1-20241114-C00326
    Figure US20240376128A1-20241114-C00327
    Figure US20240376128A1-20241114-C00328
    Figure US20240376128A1-20241114-C00329
    Figure US20240376128A1-20241114-C00330
    Figure US20240376128A1-20241114-C00331
    Figure US20240376128A1-20241114-C00332
    Figure US20240376128A1-20241114-C00333
    Figure US20240376128A1-20241114-C00334
    Figure US20240376128A1-20241114-C00335
    Figure US20240376128A1-20241114-C00336
    Figure US20240376128A1-20241114-C00337
    Figure US20240376128A1-20241114-C00338
    or
    Figure US20240376128A1-20241114-C00339
      • Wherein, said R4 is independently optionally substituted with 1, 2, 3 or 4 R41;
      • Each of R41 is independently selected from any moiety in the Table 8:
  • TABLE 8
    —F,
    —Cl,
    methyl,
    ethyl,
    isopropyl,
    —CH═CH2,
    —C≡CH,
    —C≡CCH3,
    —C≡CD,
    —CH2C≡CH,
    —CHF2,
    —CF3,
    —CH2CF3,
    —CH2CHF2,
    —CH2CH2F,
    —CH2CH2CH2F,
    —OCF3,
    —CN,
    —CH2CH2CN,
    —NH2,
    —N(CH3)2,
    —NHCH2CH3,
    —CH2—N(CH3)2,
    —OH,
    —CH2OH,
    —CH2CH2OH,
    —OCH3,
    —OC(CH3)2,
    —CH2CH(CH3)2,
    —CH(CH3)CH2CH3,
    —CH2OCH3,
    —SH,
    —SCH3,
    —SCF3,
    —OCHF2,
    —CH(CF3)OCH3,
    —C(CH3)2OH,
    —CF(CH3)2,
    —OCH(CH3)2,
    cyclopropyl,
    Figure US20240376128A1-20241114-C00340
    Figure US20240376128A1-20241114-C00341
    Figure US20240376128A1-20241114-C00342
    Figure US20240376128A1-20241114-C00343
    Figure US20240376128A1-20241114-C00344
    or
    Figure US20240376128A1-20241114-C00345
  • [23]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [22], wherein, R4 is selected from any moiety in the Table 9:
  • TABLE 9
    Figure US20240376128A1-20241114-C00346
    Figure US20240376128A1-20241114-C00347
    Figure US20240376128A1-20241114-C00348
    Figure US20240376128A1-20241114-C00349
    Figure US20240376128A1-20241114-C00350
    Figure US20240376128A1-20241114-C00351
    Figure US20240376128A1-20241114-C00352
    Figure US20240376128A1-20241114-C00353
    Figure US20240376128A1-20241114-C00354
    Figure US20240376128A1-20241114-C00355
    Figure US20240376128A1-20241114-C00356
    Figure US20240376128A1-20241114-C00357
    Figure US20240376128A1-20241114-C00358
    Figure US20240376128A1-20241114-C00359
    Figure US20240376128A1-20241114-C00360
    Figure US20240376128A1-20241114-C00361
    Figure US20240376128A1-20241114-C00362
    Figure US20240376128A1-20241114-C00363
    Figure US20240376128A1-20241114-C00364
    Figure US20240376128A1-20241114-C00365
    Figure US20240376128A1-20241114-C00366
    Figure US20240376128A1-20241114-C00367
    Figure US20240376128A1-20241114-C00368
    Figure US20240376128A1-20241114-C00369
    Figure US20240376128A1-20241114-C00370
    Figure US20240376128A1-20241114-C00371
    Figure US20240376128A1-20241114-C00372
    Figure US20240376128A1-20241114-C00373
    Figure US20240376128A1-20241114-C00374
    Figure US20240376128A1-20241114-C00375
    Figure US20240376128A1-20241114-C00376
    Figure US20240376128A1-20241114-C00377
    Figure US20240376128A1-20241114-C00378
    Figure US20240376128A1-20241114-C00379
    Figure US20240376128A1-20241114-C00380
    Figure US20240376128A1-20241114-C00381
    Figure US20240376128A1-20241114-C00382
    Figure US20240376128A1-20241114-C00383
    Figure US20240376128A1-20241114-C00384
    Figure US20240376128A1-20241114-C00385
    Figure US20240376128A1-20241114-C00386
    Figure US20240376128A1-20241114-C00387
    Figure US20240376128A1-20241114-C00388
    Figure US20240376128A1-20241114-C00389
    Figure US20240376128A1-20241114-C00390
    Figure US20240376128A1-20241114-C00391
    Figure US20240376128A1-20241114-C00392
    Figure US20240376128A1-20241114-C00393
    Figure US20240376128A1-20241114-C00394
    Figure US20240376128A1-20241114-C00395
    Figure US20240376128A1-20241114-C00396
    Figure US20240376128A1-20241114-C00397
    Figure US20240376128A1-20241114-C00398
    Figure US20240376128A1-20241114-C00399
    Figure US20240376128A1-20241114-C00400
    Figure US20240376128A1-20241114-C00401
    Figure US20240376128A1-20241114-C00402
    Figure US20240376128A1-20241114-C00403
    Figure US20240376128A1-20241114-C00404
    Figure US20240376128A1-20241114-C00405
    Figure US20240376128A1-20241114-C00406
    Figure US20240376128A1-20241114-C00407
    Figure US20240376128A1-20241114-C00408
    Figure US20240376128A1-20241114-C00409
    Figure US20240376128A1-20241114-C00410
    Figure US20240376128A1-20241114-C00411
    Figure US20240376128A1-20241114-C00412
    Figure US20240376128A1-20241114-C00413
    Figure US20240376128A1-20241114-C00414
    Figure US20240376128A1-20241114-C00415
    Figure US20240376128A1-20241114-C00416
    Figure US20240376128A1-20241114-C00417
    Figure US20240376128A1-20241114-C00418
    Figure US20240376128A1-20241114-C00419
    Figure US20240376128A1-20241114-C00420
    Figure US20240376128A1-20241114-C00421
    Figure US20240376128A1-20241114-C00422
    Figure US20240376128A1-20241114-C00423
    Figure US20240376128A1-20241114-C00424
    Figure US20240376128A1-20241114-C00425
    Figure US20240376128A1-20241114-C00426
    Figure US20240376128A1-20241114-C00427
    Figure US20240376128A1-20241114-C00428
    Figure US20240376128A1-20241114-C00429
    Figure US20240376128A1-20241114-C00430
    Figure US20240376128A1-20241114-C00431
    Figure US20240376128A1-20241114-C00432
    Figure US20240376128A1-20241114-C00433
    Figure US20240376128A1-20241114-C00434
    Figure US20240376128A1-20241114-C00435
    Figure US20240376128A1-20241114-C00436
    Figure US20240376128A1-20241114-C00437
    Figure US20240376128A1-20241114-C00438
    Figure US20240376128A1-20241114-C00439
    Figure US20240376128A1-20241114-C00440
    Figure US20240376128A1-20241114-C00441
    Figure US20240376128A1-20241114-C00442
    Figure US20240376128A1-20241114-C00443
    Figure US20240376128A1-20241114-C00444
    Figure US20240376128A1-20241114-C00445
    Figure US20240376128A1-20241114-C00446
    Figure US20240376128A1-20241114-C00447
    Figure US20240376128A1-20241114-C00448
    Figure US20240376128A1-20241114-C00449
    Figure US20240376128A1-20241114-C00450
    Figure US20240376128A1-20241114-C00451
    Figure US20240376128A1-20241114-C00452
    Figure US20240376128A1-20241114-C00453
    Figure US20240376128A1-20241114-C00454
    Figure US20240376128A1-20241114-C00455
    Figure US20240376128A1-20241114-C00456
    Figure US20240376128A1-20241114-C00457
    Figure US20240376128A1-20241114-C00458
    Figure US20240376128A1-20241114-C00459
    Figure US20240376128A1-20241114-C00460
    Figure US20240376128A1-20241114-C00461
    Figure US20240376128A1-20241114-C00462
    Figure US20240376128A1-20241114-C00463
    Figure US20240376128A1-20241114-C00464
    Figure US20240376128A1-20241114-C00465
    Figure US20240376128A1-20241114-C00466
    Figure US20240376128A1-20241114-C00467
    Figure US20240376128A1-20241114-C00468
    Figure US20240376128A1-20241114-C00469
    Figure US20240376128A1-20241114-C00470
    Figure US20240376128A1-20241114-C00471
    Figure US20240376128A1-20241114-C00472
    Figure US20240376128A1-20241114-C00473
    Figure US20240376128A1-20241114-C00474
    Figure US20240376128A1-20241114-C00475
    Figure US20240376128A1-20241114-C00476
    Figure US20240376128A1-20241114-C00477
    Figure US20240376128A1-20241114-C00478
    Figure US20240376128A1-20241114-C00479
    Figure US20240376128A1-20241114-C00480
    Figure US20240376128A1-20241114-C00481
    Figure US20240376128A1-20241114-C00482
    Figure US20240376128A1-20241114-C00483
    Figure US20240376128A1-20241114-C00484
    Figure US20240376128A1-20241114-C00485
    Figure US20240376128A1-20241114-C00486
    Figure US20240376128A1-20241114-C00487
    Figure US20240376128A1-20241114-C00488
    Figure US20240376128A1-20241114-C00489
    Figure US20240376128A1-20241114-C00490
    Figure US20240376128A1-20241114-C00491
    Figure US20240376128A1-20241114-C00492
    Figure US20240376128A1-20241114-C00493
    Figure US20240376128A1-20241114-C00494
    Figure US20240376128A1-20241114-C00495
    Figure US20240376128A1-20241114-C00496
    Figure US20240376128A1-20241114-C00497
    Figure US20240376128A1-20241114-C00498
    Figure US20240376128A1-20241114-C00499
    Figure US20240376128A1-20241114-C00500
    Figure US20240376128A1-20241114-C00501
    Figure US20240376128A1-20241114-C00502
    Figure US20240376128A1-20241114-C00503
    Figure US20240376128A1-20241114-C00504
    Figure US20240376128A1-20241114-C00505
    Figure US20240376128A1-20241114-C00506
    Figure US20240376128A1-20241114-C00507
    Figure US20240376128A1-20241114-C00508
    Figure US20240376128A1-20241114-C00509
    Figure US20240376128A1-20241114-C00510
    Figure US20240376128A1-20241114-C00511
    Figure US20240376128A1-20241114-C00512
    Figure US20240376128A1-20241114-C00513
    Figure US20240376128A1-20241114-C00514
    Figure US20240376128A1-20241114-C00515
    Figure US20240376128A1-20241114-C00516
    Figure US20240376128A1-20241114-C00517
    Figure US20240376128A1-20241114-C00518
    Figure US20240376128A1-20241114-C00519
    Figure US20240376128A1-20241114-C00520
    Figure US20240376128A1-20241114-C00521
    Figure US20240376128A1-20241114-C00522
    Figure US20240376128A1-20241114-C00523
    Figure US20240376128A1-20241114-C00524
    Figure US20240376128A1-20241114-C00525
    Figure US20240376128A1-20241114-C00526
    Figure US20240376128A1-20241114-C00527
    Figure US20240376128A1-20241114-C00528
    Figure US20240376128A1-20241114-C00529
    Figure US20240376128A1-20241114-C00530
    Figure US20240376128A1-20241114-C00531
    Figure US20240376128A1-20241114-C00532
    Figure US20240376128A1-20241114-C00533
    Figure US20240376128A1-20241114-C00534
    Figure US20240376128A1-20241114-C00535
    Figure US20240376128A1-20241114-C00536
    Figure US20240376128A1-20241114-C00537
    Figure US20240376128A1-20241114-C00538
    Figure US20240376128A1-20241114-C00539
    Figure US20240376128A1-20241114-C00540
    Figure US20240376128A1-20241114-C00541
    Figure US20240376128A1-20241114-C00542
    Figure US20240376128A1-20241114-C00543
    Figure US20240376128A1-20241114-C00544
    Figure US20240376128A1-20241114-C00545
    Figure US20240376128A1-20241114-C00546
    Figure US20240376128A1-20241114-C00547
    Figure US20240376128A1-20241114-C00548
    Figure US20240376128A1-20241114-C00549
    Figure US20240376128A1-20241114-C00550
    Figure US20240376128A1-20241114-C00551
    Figure US20240376128A1-20241114-C00552
    Figure US20240376128A1-20241114-C00553
    Figure US20240376128A1-20241114-C00554
    Figure US20240376128A1-20241114-C00555
    Figure US20240376128A1-20241114-C00556
    Figure US20240376128A1-20241114-C00557
    Figure US20240376128A1-20241114-C00558
    Figure US20240376128A1-20241114-C00559
    Figure US20240376128A1-20241114-C00560
    Figure US20240376128A1-20241114-C00561
    Figure US20240376128A1-20241114-C00562
    Figure US20240376128A1-20241114-C00563
    Figure US20240376128A1-20241114-C00564
    Figure US20240376128A1-20241114-C00565
    Figure US20240376128A1-20241114-C00566
    Figure US20240376128A1-20241114-C00567
    Figure US20240376128A1-20241114-C00568
    Figure US20240376128A1-20241114-C00569
    Figure US20240376128A1-20241114-C00570
    Figure US20240376128A1-20241114-C00571
    Figure US20240376128A1-20241114-C00572
    Figure US20240376128A1-20241114-C00573
    Figure US20240376128A1-20241114-C00574
    Figure US20240376128A1-20241114-C00575
    Figure US20240376128A1-20241114-C00576
    Figure US20240376128A1-20241114-C00577
    Figure US20240376128A1-20241114-C00578
    Figure US20240376128A1-20241114-C00579
    Figure US20240376128A1-20241114-C00580
    Figure US20240376128A1-20241114-C00581
    Figure US20240376128A1-20241114-C00582
    Figure US20240376128A1-20241114-C00583
    Figure US20240376128A1-20241114-C00584
    Figure US20240376128A1-20241114-C00585
    Figure US20240376128A1-20241114-C00586
    Figure US20240376128A1-20241114-C00587
    Figure US20240376128A1-20241114-C00588
    Figure US20240376128A1-20241114-C00589
    Figure US20240376128A1-20241114-C00590
    Figure US20240376128A1-20241114-C00591
    Figure US20240376128A1-20241114-C00592
    Figure US20240376128A1-20241114-C00593
    Figure US20240376128A1-20241114-C00594
    Figure US20240376128A1-20241114-C00595
    Figure US20240376128A1-20241114-C00596
    Figure US20240376128A1-20241114-C00597
    Figure US20240376128A1-20241114-C00598
    Figure US20240376128A1-20241114-C00599
    Figure US20240376128A1-20241114-C00600
    Figure US20240376128A1-20241114-C00601
    Figure US20240376128A1-20241114-C00602
    Figure US20240376128A1-20241114-C00603
    Figure US20240376128A1-20241114-C00604
    Figure US20240376128A1-20241114-C00605
    Figure US20240376128A1-20241114-C00606
    Figure US20240376128A1-20241114-C00607
    Figure US20240376128A1-20241114-C00608
    Figure US20240376128A1-20241114-C00609
    Figure US20240376128A1-20241114-C00610
    Figure US20240376128A1-20241114-C00611
    Figure US20240376128A1-20241114-C00612
    Figure US20240376128A1-20241114-C00613
    Figure US20240376128A1-20241114-C00614
    Figure US20240376128A1-20241114-C00615
    Figure US20240376128A1-20241114-C00616
    Figure US20240376128A1-20241114-C00617
    Figure US20240376128A1-20241114-C00618
    Figure US20240376128A1-20241114-C00619
    Figure US20240376128A1-20241114-C00620
    Figure US20240376128A1-20241114-C00621
    Figure US20240376128A1-20241114-C00622
    Figure US20240376128A1-20241114-C00623
    Figure US20240376128A1-20241114-C00624
    Figure US20240376128A1-20241114-C00625
    Figure US20240376128A1-20241114-C00626
    Figure US20240376128A1-20241114-C00627
    Figure US20240376128A1-20241114-C00628
    Figure US20240376128A1-20241114-C00629
    Figure US20240376128A1-20241114-C00630
    Figure US20240376128A1-20241114-C00631
    Figure US20240376128A1-20241114-C00632
    Figure US20240376128A1-20241114-C00633
    Figure US20240376128A1-20241114-C00634
    Figure US20240376128A1-20241114-C00635
    Figure US20240376128A1-20241114-C00636
    Figure US20240376128A1-20241114-C00637
    Figure US20240376128A1-20241114-C00638
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    Figure US20240376128A1-20241114-C01044
    Figure US20240376128A1-20241114-C01045
    Figure US20240376128A1-20241114-C01046
    Figure US20240376128A1-20241114-C01047
    Figure US20240376128A1-20241114-C01048
    Figure US20240376128A1-20241114-C01049
    Figure US20240376128A1-20241114-C01050
    Figure US20240376128A1-20241114-C01051
    Figure US20240376128A1-20241114-C01052
    Figure US20240376128A1-20241114-C01053
    Figure US20240376128A1-20241114-C01054
    Figure US20240376128A1-20241114-C01055
    Figure US20240376128A1-20241114-C01056
    Figure US20240376128A1-20241114-C01057
    Figure US20240376128A1-20241114-C01058
    Figure US20240376128A1-20241114-C01059
    Figure US20240376128A1-20241114-C01060
    Figure US20240376128A1-20241114-C01061
    Figure US20240376128A1-20241114-C01062
    Figure US20240376128A1-20241114-C01063
    Figure US20240376128A1-20241114-C01064
    Figure US20240376128A1-20241114-C01065
    Figure US20240376128A1-20241114-C01066
    Figure US20240376128A1-20241114-C01067
    Figure US20240376128A1-20241114-C01068
    Figure US20240376128A1-20241114-C01069
    Figure US20240376128A1-20241114-C01070
    Figure US20240376128A1-20241114-C01071
    Figure US20240376128A1-20241114-C01072
    Figure US20240376128A1-20241114-C01073
    Figure US20240376128A1-20241114-C01074
    Figure US20240376128A1-20241114-C01075
    Figure US20240376128A1-20241114-C01076
    Figure US20240376128A1-20241114-C01077
    Figure US20240376128A1-20241114-C01078
    Figure US20240376128A1-20241114-C01079
    Figure US20240376128A1-20241114-C01080
    Figure US20240376128A1-20241114-C01081
    Figure US20240376128A1-20241114-C01082
    Figure US20240376128A1-20241114-C01083
    Figure US20240376128A1-20241114-C01084
    Figure US20240376128A1-20241114-C01085
    Figure US20240376128A1-20241114-C01086
    Figure US20240376128A1-20241114-C01087
    Figure US20240376128A1-20241114-C01088
    Figure US20240376128A1-20241114-C01089
    Figure US20240376128A1-20241114-C01090
    Figure US20240376128A1-20241114-C01091
    Figure US20240376128A1-20241114-C01092
    Figure US20240376128A1-20241114-C01093
    Figure US20240376128A1-20241114-C01094
    Figure US20240376128A1-20241114-C01095
    Figure US20240376128A1-20241114-C01096
    Figure US20240376128A1-20241114-C01097
    Figure US20240376128A1-20241114-C01098
    Figure US20240376128A1-20241114-C01099
    Figure US20240376128A1-20241114-C01100
    Figure US20240376128A1-20241114-C01101
    or
    Figure US20240376128A1-20241114-C01102
  • [24]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [23], wherein, R4 is selected from any moiety in the Table 10:
  • TABLE 10
    Figure US20240376128A1-20241114-C01103
    Figure US20240376128A1-20241114-C01104
    Figure US20240376128A1-20241114-C01105
    Figure US20240376128A1-20241114-C01106
    Figure US20240376128A1-20241114-C01107
    Figure US20240376128A1-20241114-C01108
    Figure US20240376128A1-20241114-C01109
    Figure US20240376128A1-20241114-C01110
    Figure US20240376128A1-20241114-C01111
    Figure US20240376128A1-20241114-C01112
    Figure US20240376128A1-20241114-C01113
    Figure US20240376128A1-20241114-C01114
    Figure US20240376128A1-20241114-C01115
    Figure US20240376128A1-20241114-C01116
  • [25]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [24], wherein, R51 is selected from hydrogen, deuterium, —F, —Cl, —Br, —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —CN, —NHC1-3alkyl, —N(C1-3alkyl)2, —OC1-3alkyl, —O-(3-6 membered cycloalkyl), —SC1-3alkyl, —S(haloC1-3alkyl) or 3-6 membered cycloalkyl; wherein, said —C1-3alkyl or 3-6 membered cycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from halogen, —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl or —S(haloC1-3alkyl).
  • [26]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [25], wherein, R51 is selected from hydrogen, deuterium, —Cl, —CN, —CH3, —CHF2, —CH2F, —CF3, —CH2OH, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —NHCH3, —N(CH3)2, —OCF3, —CN, —CH2CN, —COOH, —CONH2, —COOCH3,
  • Figure US20240376128A1-20241114-C01117
  • [27]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [26], wherein, R51 is selected from hydrogen.
  • [28]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [27], wherein, the compound is selected from any one of the following formulas:
  • Figure US20240376128A1-20241114-C01118
    Figure US20240376128A1-20241114-C01119
    Figure US20240376128A1-20241114-C01120
  • [29]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [28], wherein, R52 is selected from halogen.
  • [30]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29], wherein, R52 is selected from —F.
  • [31]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [30], wherein, the compound is selected from any one of the following formulas:
  • Figure US20240376128A1-20241114-C01121
    Figure US20240376128A1-20241114-C01122
    Figure US20240376128A1-20241114-C01123
  • [32]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [31], wherein, the prodrug is selected from any one of the following formulas:
  • Figure US20240376128A1-20241114-C01124
    Figure US20240376128A1-20241114-C01125
    Figure US20240376128A1-20241114-C01126
    Figure US20240376128A1-20241114-C01127
  • R43 at each occurrence is independently selected from
  • Figure US20240376128A1-20241114-C01128
  • R4c is selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R4j;
      • R4d and R4e are each selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C(═O)C1-6alkyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more 14;
      • R4f and R4g are each selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C(═O)C1-6alkyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more 14;
      • R4h, R4i, R4m, R4n and R4p are each selected from hydrogen, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
      • Optionally, R4f and R4g together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2 and optionally substituted with one or more R4j;
      • Optionally, R4f and R4h together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2 and optionally substituted with one or more R4j;
      • R4j at each occurrence is independently selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, oxo, —NO2, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 substituents selected from halogen; —C1-6alkyl; haloC1-6alkyl; —CN; oxo; —OH; —NH2; —NH(C1-6alkyl); —N(C1-6alkyl)2; —OC1-6alkyl; or —C1-6alkyl substituted with 1, 2 or 3 substituents selected from halogen, haloC1-6alkyl, —CN, —OH, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2 or —OC1-6alkyl;
      • Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(═O) or S(═O)2.
  • [33]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of [32], wherein, —OR43 is selected from any moiety in the Table 11:
  • TABLE 11
    Figure US20240376128A1-20241114-C01129
    Figure US20240376128A1-20241114-C01130
    Figure US20240376128A1-20241114-C01131
    Figure US20240376128A1-20241114-C01132
    Figure US20240376128A1-20241114-C01133
    Figure US20240376128A1-20241114-C01134
    Figure US20240376128A1-20241114-C01135
    Figure US20240376128A1-20241114-C01136
    Figure US20240376128A1-20241114-C01137
    Figure US20240376128A1-20241114-C01138
    Figure US20240376128A1-20241114-C01139
    Figure US20240376128A1-20241114-C01140
    Figure US20240376128A1-20241114-C01141
    Figure US20240376128A1-20241114-C01142
    Figure US20240376128A1-20241114-C01143
    Figure US20240376128A1-20241114-C01144
    Figure US20240376128A1-20241114-C01145
    Figure US20240376128A1-20241114-C01146
    Figure US20240376128A1-20241114-C01147
  • [34]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of [32] or [33], wherein, the moiety of
  • Figure US20240376128A1-20241114-C01148
  • is selected from any moiety in the Table 12:
  • TABLE 12
    Figure US20240376128A1-20241114-C01149
    Figure US20240376128A1-20241114-C01150
    Figure US20240376128A1-20241114-C01151
    Figure US20240376128A1-20241114-C01152
    Figure US20240376128A1-20241114-C01153
    Figure US20240376128A1-20241114-C01154
    Figure US20240376128A1-20241114-C01155
    Figure US20240376128A1-20241114-C01156
    Figure US20240376128A1-20241114-C01157
    Figure US20240376128A1-20241114-C01158
    Figure US20240376128A1-20241114-C01159
    Figure US20240376128A1-20241114-C01160
    Figure US20240376128A1-20241114-C01161
    Figure US20240376128A1-20241114-C01162
    Figure US20240376128A1-20241114-C01163
    Figure US20240376128A1-20241114-C01164
    Figure US20240376128A1-20241114-C01165
    Figure US20240376128A1-20241114-C01166
    Figure US20240376128A1-20241114-C01167
  • [35]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [34], wherein, the conjugated form thereof is a PROTAC molecule.
  • [36]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [35] selected from any compound in the Table 13:
  • TABLE 13
    ID IUPAC Name
    1 4-(4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)
    methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2,2,2-trifluoroacetic acid;
    2 4-(4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    3 4-(4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    4 4-(4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    5 5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    6 5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    7 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    8 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    9 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    10 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    11 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    12 4-(4-(cyclopropyl(methyl-d3)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2,2,2-trifluoroacetic acid;
    13 4-(4-(cyclopropyl(methyl-d3)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    14 5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    15 5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    16 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    17 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    18 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    19 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    20 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    21 4-(4-(ethyl(trans-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    22 4-(4-(ethyl(trans-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    23 4-(4-(ethyl((1R,2R)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    24 4-(4-(ethyl((1R,2R)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    25 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    26 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    27 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    28 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    29 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    30 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    31 4-(4-(cyclopropyl(methyl-d3)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl methylcarbamate;
    32 (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((trans-2-
    fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol
    2,2,2-trifluoroacetic acid;
    33 (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((trans-2-
    fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol;
    34 (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((1R,2R)-2-
    fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol
    2,2,2-trifluoroacetic acid;
    35 (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((1R,2R)-2-
    fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol;
    36 (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((1S,2S)-2-
    fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol
    2,2,2-trifluoroacetic acid;
    37 (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((1S,2S)-2-
    fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol;
    38 (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((2-
    fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol;
    39 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid;
    40 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    41 4-(4-((2,2-difluorocyclopropyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    42 4-(4-((2,2-difluorocyclopropyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    43 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    44 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    45 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    46 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    47 4-(4-(cyclopropyl(cyclopropylmethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    48 4-(4-(cyclopropyl(cyclopropylmethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    49 6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    50 6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol;
    51 6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    52 6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol;
    53 6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    54 6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol;
    55 6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol;
    56 5-ethyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    57 5-ethyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    58 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    59 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    60 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    61 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    62 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    63 4-(4-(cyclopropyl(2,2-difluoroethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    64 4-(4-(cyclopropyl(2,2-difluoroethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7
    a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    65 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formic acid;
    66 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    67 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl(1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    68 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    methylcarbamate 2,2,2-trifluoroacetic acid;
    69 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    methylcarbamate;
    70 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl methylcarbamate;
    71 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    dimethylcarbamate;
    72 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    dimethylcarbamate 2,2,2-trifluoroacetic acid;
    73 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    dimethylcarbamate;
    74 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((2-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    75 ((5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)methyl dihydrogen phosphate 2,2,2-trifluoroacetic acid;
    76 ((5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl
    dihydrogen phosphate;
    77 ((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl
    dihydrogen phosphate 2,2,2-trifluoroacetic acid;
    78 ((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl
    dihydrogen phosphate;
    79 ((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl
    dihydrogen phosphate 2,2,2-trifluoroacetic acid;
    80 ((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl
    dihydrogen phosphate;
    81 ((5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl
    dihydrogen phosphate;
    82 Di-tert-butyl
    (((5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl)
    phosphate 2,2,2-trifluoroacetic acid;
    83 Di-tert-butyl
    (((5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)methyl) phosphate;
    84 Di-tert-butyl
    (((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)methyl) phosphate 2,2,2-trifluoroacetic acid;
    85 Di-tert-butyl
    (((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)methyl) phosphate;
    86 Di-tert-butyl
    (((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)methyl) phosphate 2,2,2-trifluoroacetic acid;
    87 Di-tert-butyl
    (((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)methyl) phosphate;
    88 Di-tert-butyl
    (((5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl) phosphate;
    89 5-ethynyl-6-fluoro-4-(8-fluoro-4-((1-(fluoromethyl)cyclopropyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    90 4-(4-(cyclopropyl(methyl-d3)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    91 4-(4-(cyclopropyl(methyl-d3)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    92 4-(5-chloro-4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2,2,2-trifluoroacetic acid;
    93 4-(5-chloro-4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    94 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-
    methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    95 4-(cyclopropyl(methyl)amino)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carbonitrile;
    96 4-(4-(cyclopropyl(2-methoxyethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    97 4-(4-(cyclopropyl(2-methoxyethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    98 4-(4-(cyclopropyl(2-fluoroethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2,2,2-trifluoroacetic acid;
    99 4-(4-(cyclopropyl(2-fluoroethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    100 Ethyl
    N-cyclopropyl-N-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)glycinate
    2,2,2-trifluoroacetic acid;
    101 Ethyl
    N-cyclopropyl-N-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)glycinate;
    102 N-cyclopropyl-N-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)acetamide
    2,2,2-trifluoroacetic acid;
    103 N-cyclopropyl-N-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)acetamide;
    104 2-(cyclopropyl(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)acetonitrile
    2,2,2-trifluoroacetic acid;
    105 2-(cyclopropyl(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)acetonitrile;
    106 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((trans-2-methoxycyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    107 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1S,2S)-2-methoxycyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    108 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1R,2R)-2-methoxycyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    109 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((2-methoxycyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    110 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((trans-2-(methoxymethyl)cyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    111 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((trans-2-(methoxymethyl)cyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    112 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1R,2R)-2-(methoxymethyl)cyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    113 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1R,2R)-2-(methoxymethyl)cyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    114 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1S,2S)-2-(methoxymethyl)cyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    115 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1S,2S)-2-(methoxymethyl)cyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    116 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((2-(methoxymethyl)cyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    117 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl(trans-2-(trifluoromethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    118 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl(trans-2-(trifluoromethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    119 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl((1S,2S)-2-(trifluoromethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    120 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl((1S,2S)-2-(trifluoromethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    121 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl((1R,2R)-2-(trifluoromethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    122 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl((1R,2R)-2-(trifluoromethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    123 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl(2-(trifluoromethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    124 trans-2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropane-1-carbonitrile
    2,2,2-trifluoroacetic acid;
    125 trans-2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropane-1-carbonitrile;
    126 (1S,2S)-2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropane-1-carbonitrile
    2,2,2-trifluoroacetic acid;
    127 (1S,2S)-2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropane-1-carbonitrile;
    128 (1R,2R)-2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropane-1-carbonitrile
    2,2,2-trifluoroacetic acid;
    129 (1R,2R)-2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropane-1-carbonitrile;
    130 2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropane-1-carbonitrile;
    131 4-(4-(cyclopropyl(ethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    132 4-(4-(dicyclopropylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    133 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl(2-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    134 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1S,2S)-2-hydroxycyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    135 4-(4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)
    methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    136 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((2-hydroxycyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    137 7-(4-ethynyl-1H-indol-3-yl)-8-fluoro-N-((1S,2S)-2-fluorocyclopropyl)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine;
    138 7-(4-ethynyl-1H-indol-3-yl)-8-fluoro-N-((1S,2S)-2-fluorocyclopropyl)-N-methyl-2-((1-
    (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-amine;
    139 7-(4-ethyl-1H-indol-3-yl)-8-fluoro-N-((1S,2S)-2-fluorocyclopropyl)-N-methyl-2-((1-
    (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-amine;
    140 7-(4-ethynyl-5-fluoro-1H-indol-3-yl)-8-fluoro-N-((1S,2S)-2-fluorocyclopropyl)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine;
    141 7-(4-ethyl-5-fluoro-1H-indol-3-yl)-8-fluoro-N-((1S,2S)-2-fluorocyclopropyl)-N-methyl-2-((1-
    (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-amine;
    142 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    143 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    144 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    145 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((2-hydroxy-2-methylcyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    146 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    147 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    148 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    149 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    150 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    151 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    152 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    153 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    154 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    155 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    156 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    157 4-(4-((2-(difluoromethyl)cyclopropyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    158 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-(fluoromethyl)cyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    159 1-(2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropyl)ethan-1-one;
    160 2-(2-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropyl)acetonitrile;
    161 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl((1S,2S)-2-(methylamino)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    162 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl((1S,2S)-2-(methylthio)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    163 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    164 4-(5-cyclopropoxy-8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    165 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(methylthio)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    166 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(methylamino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    167 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(trifluoromethoxy)pyrido[4,3-d]pyrimidin-7-
    yl)naphthalen-2-ol;
    168 4-(5-cyclopropyl-8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    169 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    170 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-
    2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carbonitrile;
    171 4-(5-(difluoromethyl)-8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    172 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-5-(fluoromethyl)-2-
    (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    173 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(hydroxymethyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    174 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-
    2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carboxylic acid;
    175 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-
    2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carboxamide;
    176 methyl
    7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((1S,2S)-2-
    fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidine-5-carboxylate;
    177 4-(4-(((2R,3R)-2,3-difluorocyclopropyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    178 4-(4-(((1s,2R,3S)-2,3-difluorocyclopropyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    179 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S,3R)-2-fluoro-3-methylcyclopropyl)(methyl)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    180 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S,3S)-2-fluoro-3-methylcyclopropyl)(methyl)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    181 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    182 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    183 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    184 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    185 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    186 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    187 5-ethynyl-6,7-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)-4-((2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    188 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    189 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    190 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    191 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    192 5-ethynyl-6,7-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)-4-((2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    193 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    194 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    195 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    196 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    197 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    198 5-ethynyl-6,7-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    199 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    200 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    201 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    202 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    203 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    204 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    205 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    206 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    207 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    208 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    209 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    210 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    211 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    212 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    213 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6,7-difluoronaphthalen-2-ol;
    214 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    215 5-ethynyl-6,7-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    216 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-
    2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    217 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    218 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-
    2-(methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    219 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    220 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    221 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    222 5-ethynyl-6,7-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    223 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    224 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    225 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    226 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    227 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    228 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    229 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    230 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    231 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    232 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    233 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    234 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    235 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    236 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    237 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    238 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    239 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    240 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    241 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    242 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    243 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    244 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    245 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    246 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    247 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    248 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    249 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    250 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    251 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    252 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    253 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    254 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    255 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    256 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    257 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    258 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    259 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    260 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    261 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    262 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    263 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    264 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    265 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    266 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    267 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    268 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    269 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    270 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    271 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    272 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    273 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    274 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    275 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    276 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    277 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    278 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    279 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    280 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    281 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    282 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    283 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    284 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1
    H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    285 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    286 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    287 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    288 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    289 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    290 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    291 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    292 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    293 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    294 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    295 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    296 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    297 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    298 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    299 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    300 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    301 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    302 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    303 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    304 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    305 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    306 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    307 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    308 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    309 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    310 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    311 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    312 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    313 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    314 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    315 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    316 4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(((1S,2S)-
    2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    317 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    318 4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(((1S,2S)-
    2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    319 5-bromo-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    320 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    321 5-bromo-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    322 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(((1S,2S)-
    2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    323 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    324 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(((1S,2S)-
    2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    325 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    326 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    327 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1S,2S)-2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    328 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    329 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    330 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    331 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    332 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    333 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    334 5-ethynyl-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    335 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    336 5-ethynyl-4-(8-fluoro-2-(((2R,7aS)-2-fluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-
    4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    337 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    338 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    339 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    340 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    341 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    342 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    343 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    344 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    345 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    346 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    347 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    348 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    349 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    350 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    351 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    352 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    353 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    354 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    355 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    356 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    357 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    358 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-5,5-d2)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    359 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    360 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    361 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    362 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    363 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    364 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    365 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    366 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    367 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    368 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    369 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    370 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    371 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    372 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    373 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    374 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    375 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    376 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    377 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    378 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    379 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    380 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    381 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    382 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    383 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    384 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    385 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    386 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    387 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    388 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    389 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    390 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    391 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    392 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    393 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    394 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    395 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    396 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    397 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    398 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    399 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    400 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    401 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    402 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    403 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    404 4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methylthio)naphthalen-2-ol;
    405 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    406 5-bromo-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    407 5-bromo-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    408 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    409 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    410 5-ethyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    411 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    412 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol;
    413 5,6-difluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    414 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    415 5-chloro-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    416 5-chloro-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    417 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    418 5-ethyl-4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    419 5-ethyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorote
    trahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    420 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    421 4-(4-(ethyl((1S,2S)-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol;
    422 5-ethynyl-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    423 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    424 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    425 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    426 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    427 5-bromo-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    428 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    429 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    430 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    431 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    432 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    433 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    434 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    435 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    436 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    437 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    438 5-bromo-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    439 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    440 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    441 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    442 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    443 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    444 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    445 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-methoxytetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    446 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    447 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    448 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    449 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    450 5-bromo-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    451 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    452 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    453 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    454 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    455 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    456 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    457 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl-2-d)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    458 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    459 5-bromo-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    460 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    461 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    462 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    463 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    464 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    465 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    466 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    467 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    468 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    469 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    470 5-bromo-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    471 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    (methylthio)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    472 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    473 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    474 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    475 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    476 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-(methylthio)tetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    477 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-(methylthio)tetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    478 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    479 4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    480 5-ethynyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    481 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    482 5-bromo-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    483 5-bromo-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    484 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    485 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    486 5-ethyl-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    487 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    488 5-ethyl-4-(4-(ethyl(2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol;
    489 5-ethyl-6-fluoro-4-(8-fluoro-4-((2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    490 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    methylcarbamate;
    491 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    (tetrahydro-2H-pyran-4-yl)carbamate;
    492 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-N-((1S,2S)-2-fluorocyclopropyl)-2-
    (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine;
    493 7-(8-ethynyl-7-fluoro-3-(isopropoxymethoxy)naphthalen-1-yl)-8-fluoro-N-((1S,2S)-2-fluorocyclopropyl)-2-
    (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine;
    494 7-(8-ethynyl-7-fluoro-3-((2-methoxyethoxy)methoxy)naphthalen-1-yl)-8-fluoro-N-((1S,2S)-2-
    fluorocyclopropyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-
    methylpyrido[4,3-d]pyrimidin-4-amine;
    495 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    decanoate;
    496 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    (2-methoxyethyl)carbamate;
    497 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    (((S)-tetrahydrofuran-2-yl)methyl)carbamate;
    498 isopropyl
    (ethoxy((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)phosphoryl)-L-alaninate;
    499 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    methyl(pyridin-2-yl)carbamate;
    500 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    pyridin-2-ylcarbamate;
    501 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    4-nitrobenzenesulfonate;
    502 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    isopropylcarbamate;
    503 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    adamantane-1-carboxylate;
    504 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    2-amino-6-methylbenzoate;
    505 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    2-(dimethylamino)-2-phenylacetate;
    506 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl-3,3-d2)(methyl)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    507 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl-2-d)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    508 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl-1-d)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    509 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl sulfamate
    2,2,2-trifluoroacetic acid;
    510 ethyl2-((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)acetate 2,2,2-trifluoroacetic acid;
    511 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    (2-acetamidoethyl)(methyl)carbamate 2,2,2-trifluoroacetic acid;
    512 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-
    fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl
    methyl(2-(2,2,2-trifluoroacetamido)ethyl)carbamate 2,2,2-trifluoroacetic acid;
    513 1-(((2-((((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-
    2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-
    yl)oxy)carbonyl)(methyl)amino)ethyl)carbamoyl)oxy)ethyl isobutyrate 2,2,2-trifluoroacetic acid;
    514 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-((2-fluorotetrahydro-
    1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    515 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((2-methoxycyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
    2,2,2-trifluoroacetic acid;
    516 4-(4-((2-(benzyloxy)cyclopropyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    517 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl(spiro[2.2]pentan-1-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    518 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    (methyl(spiro[2.3]hexan-1-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    519 4-(4-((3-oxabicyclo[3.1.0]hexan-6-yl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    520 4-(4-((3-oxabicyclo[3.1.0]hexan-6-yl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    521 4-(4-(bicyclo[4.1.0]heptan-7-ylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-
    yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    522 4-(4-(bicyclo[4.1.0]heptan-7-yl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-
    7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
    523 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((1-(trifluoromethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;
    524 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-
    ((1-(methoxymethyl)cyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; or
    525 1-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-
    pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclopropane-1-carbonitrile.
  • [37]. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [36], and a pharmaceutically acceptable excipient.
  • [38]. A method for treating cancer in a subject comprising administering a therapeutically effective amount of the compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [36], or the pharmaceutical composition of [37] to a subject in need thereof.
  • [39]. A method for treating cancer in a subject in need thereof, the method comprising:
      • (a) determining whether the cancer is associated with K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification; and
      • (b) if so, administering a therapeutically effective amount of the compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [36], or the pharmaceutical composition of [37] to the subject in need thereof.
  • [40]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [36], or the pharmaceutical composition of [37] for use in therapy.
  • [41]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [36], or the pharmaceutical composition of [37] for use as a medicament.
  • [42]. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [36], or the pharmaceutical composition of [37] for use in a method for the treatment of cancer.
  • [43]. A use of the compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof of any one of [1] to [36], or the pharmaceutical composition of [37] for the treatment of cancer.
  • [44]. A use of the compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof of any one of [1] to [36], or the pharmaceutical composition of [37] for the manufacture of a medicament for the treatment of cancer.
  • [45]. The method for treating cancer of [38], the use in a method for the treatment of cancer of [42], the use for the treatment of cancer of [43], or the use for the manufacture of a medicament for the treatment of cancer of [44], wherein, said cancer is selected from pancreatic carcinoma, colorectal carcinoma, lung carcinoma (such as non-small cell lung cancer), breast carcinoma, large intestine carcinoma, stomach carcinoma, endometrial carcinoma, esophageal carcinoma or gastroesophageal junction carcinoma.
  • [46]. The method for treating cancer of [38] or [45], the use in a method for the treatment of cancer of [42] or [45], the use for the treatment of cancer of [43] or [45], or the use for the manufacture of a medicament for the treatment of cancer of [44] or [45], wherein, the cancer is associated with at least one of K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification.
  • [47]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras G12C associated cancer.
  • [48]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras G12D associated cancer.
  • [49]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras G12V associated cancer.
  • [50]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras G13D associated cancer.
  • [51]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras G12R associated cancer.
  • [52]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras G12S associated cancer.
  • [53]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras G12A associated cancer.
  • [54]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras Q61H associated cancer.
  • [55]. The method for treating cancer of [38], [45] or [46], the use in a method for the treatment of cancer of [42], [45] or [46], the use for the treatment of cancer of [43], [45] or [46], or the use for the manufacture of a medicament for the treatment of cancer of [44], [45] or [46], wherein, the cancer a K-Ras wild type amplification associated cancer.
  • [56]. A process of preparing the compound of Formula (IB) of any one of [1] to [36], comprising the steps in the Scheme 1:
  • Figure US20240376128A1-20241114-C01168
      • X1, X2 or X3 at each occurrence is independently selected from a leaving group (such as —F, —Cl, —Br, —I, —OS(O)2CF3 or -OTs); preferably, X1, X2 or X3 is selected from —Cl;
      • The definition of R2a, R2, R4, R51, R52, RS1 or Y is same as any one of [1] to [36];
      • R4′ is R4 with one or more protection groups.
  • [57]. An intermediate for preparing the compound of Formula (IB), comprising any one of the following formulas:
  • Figure US20240376128A1-20241114-C01169
  • [58]. The intermediate of [57], wherein the intermediate is selected from any compound in the Table 14:
  • TABLE 14
    Figure US20240376128A1-20241114-C01170
    Figure US20240376128A1-20241114-C01171
    Figure US20240376128A1-20241114-C01172
    Figure US20240376128A1-20241114-C01173
    Figure US20240376128A1-20241114-C01174
    Figure US20240376128A1-20241114-C01175
    Figure US20240376128A1-20241114-C01176
    Figure US20240376128A1-20241114-C01177
    Figure US20240376128A1-20241114-C01178
    Figure US20240376128A1-20241114-C01179
    Figure US20240376128A1-20241114-C01180
    Figure US20240376128A1-20241114-C01181
    Figure US20240376128A1-20241114-C01182
    Figure US20240376128A1-20241114-C01183
    Figure US20240376128A1-20241114-C01184
    Figure US20240376128A1-20241114-C01185
    Figure US20240376128A1-20241114-C01186
    Figure US20240376128A1-20241114-C01187
    Figure US20240376128A1-20241114-C01188
    Figure US20240376128A1-20241114-C01189
    Figure US20240376128A1-20241114-C01190
    Figure US20240376128A1-20241114-C01191
    Figure US20240376128A1-20241114-C01192
    Figure US20240376128A1-20241114-C01193
    Figure US20240376128A1-20241114-C01194
    Figure US20240376128A1-20241114-C01195
    Figure US20240376128A1-20241114-C01196
    Figure US20240376128A1-20241114-C01197
    Figure US20240376128A1-20241114-C01198
    Figure US20240376128A1-20241114-C01199
    Figure US20240376128A1-20241114-C01200
    Figure US20240376128A1-20241114-C01201
    Figure US20240376128A1-20241114-C01202
    Figure US20240376128A1-20241114-C01203
    Figure US20240376128A1-20241114-C01204
    Figure US20240376128A1-20241114-C01205
    Figure US20240376128A1-20241114-C01206
    Figure US20240376128A1-20241114-C01207
    Figure US20240376128A1-20241114-C01208
    Figure US20240376128A1-20241114-C01209
    Figure US20240376128A1-20241114-C01210
    Figure US20240376128A1-20241114-C01211
    Figure US20240376128A1-20241114-C01212
    Figure US20240376128A1-20241114-C01213
    Figure US20240376128A1-20241114-C01214
    Figure US20240376128A1-20241114-C01215
    Figure US20240376128A1-20241114-C01216
    Figure US20240376128A1-20241114-C01217
    Figure US20240376128A1-20241114-C01218
    Figure US20240376128A1-20241114-C01219
    Figure US20240376128A1-20241114-C01220
    Figure US20240376128A1-20241114-C01221
    Figure US20240376128A1-20241114-C01222
    Figure US20240376128A1-20241114-C01223
    Figure US20240376128A1-20241114-C01224
    Figure US20240376128A1-20241114-C01225
    Figure US20240376128A1-20241114-C01226
    Figure US20240376128A1-20241114-C01227
    Figure US20240376128A1-20241114-C01228
    Figure US20240376128A1-20241114-C01229
    Figure US20240376128A1-20241114-C01230
    Figure US20240376128A1-20241114-C01231
    Figure US20240376128A1-20241114-C01232
    Figure US20240376128A1-20241114-C01233
    Figure US20240376128A1-20241114-C01234
    Figure US20240376128A1-20241114-C01235
    Figure US20240376128A1-20241114-C01236
    Figure US20240376128A1-20241114-C01237
    Figure US20240376128A1-20241114-C01238
    Figure US20240376128A1-20241114-C01239
    Figure US20240376128A1-20241114-C01240
    Figure US20240376128A1-20241114-C01241
    Figure US20240376128A1-20241114-C01242
    Figure US20240376128A1-20241114-C01243
    Figure US20240376128A1-20241114-C01244
    Figure US20240376128A1-20241114-C01245
    Figure US20240376128A1-20241114-C01246
    Figure US20240376128A1-20241114-C01247
    Figure US20240376128A1-20241114-C01248
    Figure US20240376128A1-20241114-C01249
    Figure US20240376128A1-20241114-C01250
    Figure US20240376128A1-20241114-C01251
    Figure US20240376128A1-20241114-C01252
    • Definitions
  • Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.
  • The term “a”, “an”, “the” and similar terms, as used herein, unless otherwise indicated, are to be construed to cover both the singular and plural.
  • The term “halogen” or “halo”, as used interchangeably herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo. The preferred halogen groups include —F, —Cl and —Br.
  • The term “alkyl”, as used herein, unless otherwise indicated, refers to saturated monovalent hydrocarbon radicals having straight or branched arrangement. C1-10 in —C1-10alkyl is defined to identify the group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in a linear or branched arrangement. Non-limiting alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • The term “haloalkyl”, as used herein, unless otherwise indicated, refers to the above-mentioned alkyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as —F, —Cl or —Br). In some embodiments, the haloalkyl is interchangeable —C1-10haloalkyl or haloC1-10alkyl, wherein, C1-10 in the —C1-10haloaklyl or haloC1-10alkyl indicates that the total carbon atoms of the alkyl are 1 to 10. In some embodiments, the —C1-10haloalkyl is the —C1-6haloalkyl. In some embodiments, the —C1-6haloalkyl is the —C1-3haloalkyl. In some embodiments, the —C1-3haloalkyl is (methyl, ethyl, propyl or isopropyl) substituted with 1, 2, 3, 4, 5, or 6 —F; preferably, the —C1-3haloalkyl is —CF3.
  • The term “alkylene”, as used herein, unless otherwise indicated, refers to a divalent group obtained by removal of an additional hydrogen atom from an alkyl group defined above. In some embodiments, the alkylene is C0-6alkylene. In some embodiments, the C0-6alkylene is C0-3alkylene. The C0-6 in the front of the alkylene indicates the total carbon atoms in the alkylene are 0 to 6 and C0 indicates the two ends of the alkylene are connected directly. Non-limiting alkylene includes methylene (i.e., —CH2—), ethylene (i.e., —CH2—CH2— or —CH(CH3)—) and propylene (i.e., —CH2—CH2—CH2—, —CH(—CH2—CH3)— or —CH2—CH(CH3)—).
  • The term “alkenyl”, as used herein, unless otherwise indicated, refers to a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
  • In some embodiments, the alkenyl is —C2-10alkenyl. In some embodiments, the —C2-10alkenyl is —C2-6alkenyl which contains from 2 to 6 carbon atoms. Non-limiting alkenyl includes ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
  • The term “haloalkenyl”, as used herein, unless otherwise indicated, refers to the above-mentioned alkenyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as —F, —Cl or —Br). In some embodiments, the haloalkenyl is interchangeable —C2-10haloalkenyl or haloC2-10alkenyl, wherein, C2-10 in the —C2-10haloaklenyl or haloC2-10alkenyl indicates that the total carbon atoms of the alkenyl are 2 to 10. In some embodiments, the —C2-10haloalkenyl is the —C2-6haloalkenyl. In some embodiments, the —C2-6haloalkenyl is the —C2-3haloalkenyl. In some embodiments, the —C2-3haloalkenyl is (ethenyl or propenyl) substituted with 1, 2, 3, 4, 5, or 6 —F.
  • The term “alkynyl”, as used herein, unless otherwise indicated, refers to a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. In some embodiments, the alkynyl is —C2-10alkynyl. In some embodiments, the —C2-10alkynyl is —C2-6alkynyl which contains from 2 to 6 carbon atoms. Non-limiting alkynyl includes ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • The term “haloalkynyl”, as used herein, unless otherwise indicated, refers to the above-mentioned alkynyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as —F, —Cl or —Br). In some embodiments, the haloalkynyl is interchangeable —C2-10haloalkynyl or haloC2-10alkynyl, wherein, C2-10 in the —C2-10haloaklynyl or haloC2-10alkynyl indicates that the total carbon atoms of the alkynyl are 2 to 10. In some embodiments, the —C2-10haloalkynyl is the —C2-6haloalkynyl. In some embodiments, the —C2-6haloalkynyl is the —C2-3haloalkynyl. In some embodiments, the —C2-3haloalkynyl is (ethynyl or propynyl) substituted with 1, 2, 3, 4, 5, or 6 —F.
  • The term “alkoxy”, as used herein, unless otherwise indicated, refers to oxygen ethers formed from the previously described alkyl groups.
  • The term “haloalkoxy”, as used herein, unless otherwise indicated, refers to the above-mentioned alkoxy substituted with one or more (for 1, 2, 3, 4, 5, or 6) halogen (—F, —Cl or —Br). In some embodiment, the haloalkoxy is interchangeable —C1-10haloalkoxy or haloC1-10alkoxy. In some embodiments, the haloalkoxy is interchangeable —C1-6haloalkoxy or haloC1-6alkoxy, wherein, C1-6 in the —C1-6haloakloxy or haloC1-6alkoxy indicates that the total carbon atoms of the alkoxy are 1 to 6. In some embodiments, the —C1-6haloalkoxy is the —C1-3haloalkoxy. In some embodiments, the —C1-3haloalkoxy is (methoxy, ethoxy, propoxy or isopropoxy) substituted with 1, 2, 3, 4, 5, or 6 —F; preferably, the —C1-3haloalkoxy is —OCF3.
  • The term “carbocyclic ring”, as used herein, unless otherwise indicated, refers to a totally saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring only containing carbon atoms as ring members. The term “carbocyclyl” as used herein, unless otherwise indicated, means a monovalent group obtained by removal of a hydrogen atom on the ring carbon atom from the carbocyclic ring defined in the present invention. The carbocyclic ring is interchangeable with the carbocyclyl ring in the present invention. In some embodiments, the carbocyclic ring is a three to twenty membered (such as 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-membered) carbocyclic ring and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, one, two, three, four, five or six, are included within the present definition. The carbocyclic ring includes a cycloalkyl ring in which all ring carbon atoms are saturated, a cycloalkenyl ring which contains at least one double bond (preferred contain one double bond), and a cycloalkynyl ring which contains at least one triple bond (preferred contain one triple bond). Cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Cycloalkenyl includes but not limited to cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like. The carbocyclyl ring includes a monocyclic carbocyclyl ring, and a bicyclic or polycyclic carbocyclyl ring in which one, two or three or more atoms are shared between the rings. The term “spirocyclic carbocyclic ring” refers to a carbocyclic ring in which each of the rings only shares one ring atom with the other ring. In some embodiments, the spirocyclic ring is bicyclic spirocyclic ring. The spirocyclic carbocyclic ring includes a spirocyclic cycloalkyl ring and a spirocyclic cycloalkenyl ring and a spirocyclic cycloalkynyl ring. The term “fused carbocyclic ring” refers to a carbocyclic ring in which each of the rings shares two adjacent ring atoms with the other ring. In some embodiments, the fused ring is a bicyclic fused ring. The fused carbocyclic ring includes a fused cycloalkyl ring and a fused cycloalkenyl ring and a fused cycloalkynyl ring. A monocyclic carbocyclic ring fused with an aromatic ring (such as phenyl) is included in the definition of the fused carbocyclic ring. The term “bridged carbocyclic ring” refers to a carbocyclic ring that includes at least two bridgehead carbon ring atoms and at least one bridging carbon atom. In some embodiments, the bridged ring is bicyclic bridged ring. The bridged carbocyclic ring includes a bicyclic bridged carbocyclic ring which includes two bridgehead carbon atoms and a polycyclic bridged carbocyclic ring which includes more than two bridgehead carbon atoms. The bridged carbocyclic ring includes a bridged cycloalkyl ring, a bridged cycloalkenyl ring and a bridged cycloalkynyl ring. Examples of monocyclic carbocyclyl and bicyclic carbocyclyl include but not limit to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
  • The term “heterocyclic ring”, as used herein, unless otherwise indicated, refers to a totally saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring containing not only carbon atoms as ring members and but also containing one or more (such as 1, 2, 3, 4, 5, or 6) heteroatoms as ring members. Preferred heteroatoms include N, O, S, N-oxides, sulfur oxides, and sulfur dioxides. The term “heterocyclyl” as used herein, unless otherwise indicated, means a monovalent group obtained by removal of a 50 hydrogen atom on the ring carbon atom or the ring heteroatom from the heterocyclic ring defined in the present invention. The heterocyclic ring is interchangeable with the heterocyclyl ring in the present invention. In some embodiments, the heterocyclic ring is a three to twenty membered (such as 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-membered) heterocyclic ring and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, one, two, three, four, five or six, 55 are included within the present definition. The heterocyclic ring includes a heterocycloalkyl ring in which all ring carbon atoms are saturated, a heterocycloalkenyl ring which contains at least one double bond (preferred contain one double bond), and a heterocycloalkynyl ring which contains at least one triple bond (preferred contain one triple bond). The heterocyclyl ring includes a monocyclic heterocyclyl ring, and a bicyclic or polycyclic heterocyclyl ring in which one, two or three or more atoms are shared between the rings. The term “spirocyclic heterocyclic ring” refers to a heterocyclic ring in which each of the rings only shares one ring atom with the other ring. In some embodiments, the spirocyclic ring is bicyclic spirocyclic ring. The spirocyclic heterocyclic ring includes a spirocyclic heterocycloalkyl ring and a spirocyclic heterocycloalkenyl ring and a spirocyclic heterocycloalkynyl ring. The term “fused heterocyclic ring” refers to a heterocyclic ring in which each of the rings shares two adjacent ring atoms with the other ring. In some embodiments, the fused ring is a bicyclic fused ring. The fused heterocyclic ring includes a fused heterocycloalkyl ring and a fused heterocycloalkenyl ring and a fused heterocycloalkynyl ring. A monocyclic heterocyclic ring fused with an aromatic ring (such as phenyl) is included in the definition of the fused heterocyclic ring. The term “bridged heterocyclic ring” refers to a heterocyclic ring that includes at least two bridgehead ring atoms and at least one bridging atom. In some embodiments, the bridged ring is bicyclic bridged ring. The bridged heterocyclic ring includes a bicyclic bridged heterocyclic ring which includes two bridgehead atoms and a polycyclic bridged heterocyclic ring which includes more than two bridgehead atoms. The bridged heterocyclic ring includes a bridged heterocycloalkyl ring, a bridged heterocycloalkenyl ring and a bridged heterocycloalkynyl ring. Examples of such heterocyclyl include but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
  • The term “aryl”, as used herein, unless otherwise indicated, refers to a mono or polycyclic aromatic ring system only containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic rings. Phenyl and naphthyl are preferred aryls.
  • The term “heteroaryl”, as used herein, unless otherwise indicated, refers to an aromatic ring containing carbons and one or more (such as 1, 2, 3 or 4) heteroatoms selected from N, O or S. The heteroaryl may be monocyclic or polycyclic. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 heteroatoms. A polycyclic heteroaryl ring may contain fused ring junction, for example, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms), preferred monocyclic heteroaryl is 5 membered heteroaryl including 1, 2, 3 or 4 heteroatoms selected from N, O or S, or 6 membered heteroaryl including 1 or 2 heteroatoms selected from N. Examples of heteroaryl groups include, but not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl or isoquinolinyl.
  • The term “one or more”, as used herein, unless otherwise indicated, refers to one or more than one. In some embodiments, “one or more” refers to 1, 2, 3, 4, 5 or 6. In some embodiments, “one or more” refers to 1, 2, 3 or 4. In some embodiments, “one or more” refers to 1, 2, or 3. In some embodiments, “one or more” refers to 1 or 2. In some embodiments, “one or more” refers to 1. In some embodiments, “one or more” refers to 2. In some embodiments, “one or more” refers to 3. In some embodiments, “one or more” refers to 4. In some embodiments, “one or more” refers to 5. In some embodiments, “one or more” refers to 6.
  • The term “substituted”, as used herein, unless otherwise indicated, refers to a hydrogen atom on the carbon atom or a hydrogen atom on the nitrogen atom is replaced by a substituent. When one or more substituents are substituted on a ring in the present invention, it means that each of substituents may be respectively independently substituted on every ring atom of the ring including but not limited to a ring carbon atom or a ring nitrogen atom. In addition, when the ring is a polycyclic ring, such as a fused ring, a bridged ring or a spiro ring, each of substituents may be respectively independently substituted on every ring atom of the polycyclic ring.
  • The term “oxo” refers to oxygen atom together with the attached carbon atom forms the group.
  • The term “composition”, as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • The term “pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds in the present invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).
  • The present invention includes within its scope the prodrug of the compounds of this invention. In general, such prodrug will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
  • The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. The term “stereoisomer” as used in the present invention refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and configuration isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The invention includes all possible stereoisomers of the compound.
  • The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. The isotopes of hydrogen can be denoted as 1H (hydrogen), 2H (deuterium) and 3H (tritium). They are also commonly denoted as D for deuterium and T for tritium. In the application, CD3 denotes a methyl group wherein all of the hydrogen atoms are deuterium. Isotopes of carbon include 13C and 14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
  • The term “deuterated derivative”, used herein, unless otherwise indicated, refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom (“D”). It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivative described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated derivative” of a compound of the disclosure, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%) In some embodiments, the deuterated derivative of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5% deuterium incorporation at each designated deuterium) at least 4500, (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation) at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at lease 6333.3 (95% deuterium incorporation, at least 6466.7 (97% deuterium incorporation, or at least 6600 (99% deuterium incorporation).
  • When a tautomer of the compound in the present invention exists, the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • The “conjugated form” refers to herein that the compound described herein is conjugated to another agent through a linker or not through a linker, wherein, the compound functions as a binder or a inhibitor of K-Ras protein (including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant protein and K-Ras wild type protein) For example, the conjugated form is a PROTAC molecule, e.g. the compound is incorporated into proteolysis targeting chimeras (PROTACs). A PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. Preferably, the portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of K-Ras protein to the E3 ligase will thus result in the destruction of the K-Ras protein. The variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis.
  • The pharmaceutical compositions of the present invention comprise a compound in present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • In practice, a compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof as defined herein can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound in the present invention or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compounds of the present invention or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • The pharmaceutical carrier employed can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
  • A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound in the present invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
  • Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described herein or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
  • Unless otherwise apparent from the context, when a value is expressed as “about” X or “approximately” X, the stated value of X will be understood to be accurate to ±10%, preferably, ±5%, ±2%.
  • The term “subject” refers to an animal. In some embodiments, the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a human. A “patient” as used herein refers to a human subject. As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. In some embodiments, the subject has experienced and/or exhibited at least one symptom of cancer to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having wild type K-Ras or a K-Ras G12A, K-Ras G12C, K-Ras G12D, K-Ras G12R, K-Ras G12S, K-Ras G12V, K-Ras G13D and/or K-Ras Q61H mutation
  • The term “inhibition”, “inhibiting” or “inhibit” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • The term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • As used herein, “K-Ras G12A” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an alanine for a glycine at amino acid position 12. A “K-Ras G12A inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12A. A “K-Ras G12A associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12A mutation.
  • As used herein, “K-Ras G12C” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. A “K-Ras G12C inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12C.
  • A “K-Ras G12C associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12C mutation.
  • As used herein, “K-Ras G12D” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. A “K-Ras G12D inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12D. A “K-Ras G12D associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12D mutation.
  • As used herein, “K-Ras G12R” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an arginine for a glycine at amino acid position 12. A “K-Ras G12R inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12R. A “K-Ras G12R associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12R mutation.
  • As used herein, “K-Ras G12S” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12. A “K-Ras G12S inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12S.
  • A “K-Ras G12S associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12S mutation.
  • As used herein, “K-Ras G12V” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a valine for a glycine at amino acid position 12. A “K-Ras G12V inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12V.
  • A “K-Ras G12V associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12V mutation.
  • As used herein, “K-Ras G13D” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 13. A “K-Ras G13D inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G13D. A “K-Ras G13D associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G13D mutation.
  • As used herein, “K-Ras Q61H” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a histidine for a glutamine at amino acid position 61. A “K-Ras Q61H inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras Q61H. A “K-Ras Q61H associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras Q61H mutation.
  • All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
  • These and other aspects will become apparent from the following written description of the invention.
    • METHODS OF PREPARATION
  • Compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples which outline specific synthetic route, and the generic schemes below are meant to provide guidance to the ordinarily skilled synthetic chemist, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as necessary, well within the skill and judgment of the ordinarily skilled artisan.
    • EXAMPLES
  • The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations in the Table 15 have been used in the examples:
  • TABLE 15
    DMF N,N-dimethylformamide
    EA/EtOAc Ethyl acetate
    Hex Hexane
    MeOH Methanol
    DCM Dichloromethane
    DCE 1,2-dichloroethane
    EtOH Ethanol
    THF Tetrahydrofuran
    DIEA/DIPEA N,N-Diisopropylethylamine
    Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium
    Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-
    palladium(II)
    TFA 2,2,2-trifluoroacetic acid
    ACN/MeCN/CH3CN Acetonitrile
    Et3N/TEA Triethylamine
    NIS N-Iodosuccinimide
    DMSO Dimethyl sulfoxide
    NCS N-chlorosuccinimide
    TBSCl Tert-butyldimethylsilyl chloride
    TMSCl Trimethylsilyl chloride
    MOMCl Methoxymethyl chloride
    MsCl Methanesulfonyl chloride
    LAH Lithium aluminum hydride
    LDA Lithium diisopropylamide
    LiHMDS Lithium hexamethyldisilazide
    B2(Pin)2 Bis(pinacolato)diboron
    NFSI N-Fluorobenzenesulfonimide
    MTBE Methyl tert-butyl ether
    DMAP N,N-dimethylpyridin-4-amine
    DABCO Triethylenediamine
    TABF Tetrabutylammonium fluoride
    m-CPBA 3-Chloroperbenzoic acid
    NMP N-methylpyrrolidone
    rt/RT/R.T Room temperature
    min(s) minute(s)
    h/hr(s) hour(s)
    aq aqueous
    Sat. saturated
    TLC Thin layer chromatography
    Prep-TLC Preparative thin layer chromatography
    MOMO Methoxymethoxyl
    TIPS Triisopropylsilyl
    IPA Isopropyl alcohol
    cataCXium A Methanesulfonato(diadamantyl-n-butylphosphino)-
    Pd G3 2′-amino-1,1′-biphenyl-2-yl)palladium(II)
    4A MS 4A Molecular sieve
    • Preparation of the Intermediates
  • The intermediates
  • Figure US20240376128A1-20241114-C01253
  • were synthesized using conventional preparation method.
    • Example 1 4-(4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (“Compound 1”)
  • Figure US20240376128A1-20241114-C01254
    Figure US20240376128A1-20241114-C01255
  • To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.88 g, 19.3298 mmol) and N,N-diisopropylethylamine (7.45 g, 57.6436 mmol) in DCM (70 mL) was added N-methylcyclopropanamine hydrochloride (2.01 g, 18.6835 mmol) at 0° C., then the mixture was stirred at room temperature for 2 h. The solution was diluted with 10% aqueous NaHCO3 solution (100 mL), and the organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was slurried with 70 ml solution (EA:Hex=1:6) to give Compound 1-1 (25163 mg, 17.9820 mmol, 93.0276% yield). MS m/z: 287 [M+H]+.
  • A solution of Compound 1-1 (5.16 g, 17.9716 mmol), INT 2 (3.84 g, 24.1205 mmol) and KF (3.29 g, 56.6297 mmol) in DMSO (150 mL) was stirred at 100° C. for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated aqueous NaHCO3 solution (150 mL) and extracted with EA (150 mL). The organic layer was washed with 200 ml aqueous NaCl solution, then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was slurried with 70 ml solution (EA:Hex=1:6) to give Compound 1-2 (5.51 g, 13.4436 mmol, 74.8049% yield). MS m/z: 410 [M+H]+.
  • To a solution of Compound 1-2 (5.51 g, 13.4436 mmol) in toluene (250 mL), INT 3 (8.95 g, 17.4622 mmol), cataCXium A Pd G3 (1.46 g, 2.0048 mmol), potassium phosphate (13.23 g, 40.6054 mmol) and water (50 mL) were added. The reaction mixture was stirred at 100° C. for 20 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated aqueous NaHCO3 solution (150 mL) and extracted with EA (150 mL). The organic layer was washed with 200 ml aqueous NaCl solution then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica column (method: DCM:MeOH=1:0˜30:1) to give Compound 1-3 (8.18 g, 10.7635 mmol, 80.0643% yield). MS m/z: 760 [M+H]+. To a solution of Compound 1-3 (8.18 g, 10.7635 mmol) in DCM (100 mL) was added 4 M HCl in dioxane (15 ml) and stirred at room temperature for 1 h. The solution was diluted with 10% aqueous NaHCO3 solution (150 mL). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 1-4 (10.6 g, 14.8061 mmol, 137.5581% yield). MS m/z: 716 [M+H]+.
  • To a solution of Compound 1-4 (10.6 g, 14.8061 mmol) in DMF (100 mL) was added CsF (11.81 g, 77.7468 mmol). The reaction mixture was stirred for 20 hours at 40° C. under nitrogen atmosphere. The solution was diluted with water (80 mL) and extracted with EA (80 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.05% TFA in water, B: CH3CN, Gradient: 15% B to 15% B in 2 min, 15% B to 40% B in 28 min, 40% B to 55% B in 30 min at a flow rate of 200 mL/min, 230 n). The eluent was adjusted to pH=8 with saturated NaHCO3. The acetonitrile in the eluent was concentrated. The resulting aqueous layer was extracted with DCM and the organic layer was washed with water, then the organic layer was dried, concentrated and lyophilized to give Compound 1 (1922 mg, 3.4347 mmol, 23.1979% yield). MS m/z: 560 [M+H]+.
  • 1H NMR (400 MHz, CD3OD) δ 9.57 (s, 1H), 7.85 (dd, J=8.9, 5.8 Hz, 1H), 7.38-7.27 (m, 2H), 7.22 (s, 1H), 5.29 (d, J=54.0 Hz, 1H), 4.26 (ddd, J=30.4, 10.5, 4.3 Hz, 2H), 3.64-3.49 (m, 1H), 3.45 (s, 3H), 3.40 (d, J=4.7 Hz, 1H), 3.29 (d, J=10.2 Hz, 3H), 3.25-3.14 (m, 2H), 3.06-2.93 (m, 1H), 2.22 (dd, J=14.5, 10.0 Hz, 1H), 2.16-2.06 (m, 1H), 2.03-1.92 (m, 2H), 1.91-1.79 (m, 1H), 1.14 (d, J=6.5 Hz, 2H), 0.99-0.79 (m, 2H).
    • Example 2 4-(4-(cyclopropyl(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (“Compound 2”)
  • Figure US20240376128A1-20241114-C01256
    Figure US20240376128A1-20241114-C01257
    Figure US20240376128A1-20241114-C01258
  • A mixture of 2,6-dichloropyridin-4-amine (35.7 g, 219.0 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (93.1 g, 262.8 mmol) in DMF (357 mL) and CH3CN (357 mL) was stirred at 80° C. for 6 hours. The reaction mixture was quenched by water (400 mL) and extracted with DCM (400 mL×3). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (eluting with petroleum ether:EtOAc=30:1, v/v) to give Compound 2-1 (12.6 g, purity: about 50%). MS (ESI, m/z): 181 [M+H]+.
  • A mixture of Compound 2-1 (2.0 g, 11.05 mmol), NIS (2.98 g, 13.26 mmol) and p-toluenesulfonic acid monohydrate (105 mg, 0.55 mmol) in CH3CN (8.4 mL) was stirred at 70° C. for 4 hours under nitrogen atmosphere. The reaction mixture was quenched by water (20 mL) and extracted with EtOAc (20 mL×3). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • The residue was purified by silica gel column (eluting with petroleum ether:EtOAc=50:1-20:1, v/v) to give Compound 2-2 (3.6 g). MS (ESI, m/z): 307 [M+H]+.
  • A mixture of Compound 2-2 (1.0 g, 3.26 mmol), Pd(PPh3)2Cl2 (229 mg, 0.33 mmol) and Et3N (1.19 g, 11.77 mmol) in EtOH (17.0 mL) was stirred at 80° C. for 20 hours under carbon monoxide atmosphere (1.5 MPa) in a sealed tube. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column to give Compound 2-3 (1.2 g). MS (ESI, m/z): 253 [M+H]+.
  • A mixture of Compound 2-3 (800 mg, 3.16 mmol), trichloroacetyl isocyanate (714 mg, 3.79 mmol) in THF (8 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE to give Compound 2-4 (880 mg). MS (ESI, m/z): 442 [M+H]+.
  • A mixture of Compound 2-4 (780 mg, 1.77 mmol), NH3/MeOH (1.26 mL, 7M, 8.85 mmol) and MeOH (7.8 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE to give Compound 2-5 (550 mg). MS (ESI, m/z): 250 [M+H]+.
  • A mixture of Compound 2-5 (375 mg, 1.50 mmol), DIPEA (595 mg, 4.60 mmol) and POCl3 (15 mL) was stirred at 105° C. for 17 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 1,4-dioxane (5 mL) and the resulting solution was added dropwise to aq. K2CO3 (20%, 30 mL).
  • The mixture was stirred for 2 hours at RT and the pH of the mixture was adjusted to 2˜3. Then, the mixture was filtered and the filter cake was collected and dried to give Compound 2-6 (344 mg). MS (ESI, m/z): 268 [M+H]+.
  • To a solution of Compound 2-6 (201.6 mg, 0.75 mmol) in dry THF (5 mL) was added sodium methanolate (111.2 mg, 2.06 mmol) and then stirred at room temperature for 15 hours. Upon completion, the mixture was adjusted to pH 5-6 with 5% citric acid and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give Compound 2-7 (203 mg, crude). MS: m/z 264 [M+1]+.
  • To a solution of Compound 2-7 (313 mg, 1.19 mmol) in toluene (10 mL) was added DIEA (0.5 mL) and POCl3 (1 mL) and stirred for 3.5 h at 100° C. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (10 mL) and the resulting mixture was added to a solution of N-methylcyclopropanamine hydrochloride (128 mg, 1.19 mmol) and DIEA (491 mg, 3.80 mmol) in DUM (10 mL) at −5° C. The mixture was stirred at room temperature for 1.5 h. The reaction was diluted with H2O (30 mL) and extracted with DCM (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Pre-TLC to give Compound 2-8 (235 mg, 0.74 mmol). MS (ESI, m/z): 317 [M+H]+.
  • To a solution of Compound 2-8 (235 mg, 0.74 mmol) and INT 2 (132 mg, 0.83 mmol) in DMSO (10 mL) was added KF (145 mg, 2.50 mmol). The reaction mixture was stirred at 95° C. for 16 hours under nitrogen atmosphere. The resulting mixture was quenched by water (30 mL) and extracted with EA (2×30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 2-9 (124 mg, 0.28 mmol). MS (ESI, m/z): 440 [M+H]+.
  • A solution of Compound 2-9 (66 mg, 0.15 mmol), INT 3 (94 mg, 0.18 mmol), cataCXium A Pd G3 (32 mg, 43.94 μmol), Cs2CO3 (100 mg, 0.31 mmol) in toluene (4 mL) and water (1 mL) was stirred at 100° C. for 18 hours under nitrogen atmosphere. The reaction mixture was diluted with EA (30 mL) and washed with water (2×20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Pre-TLC to give Compound 2-10 (104 mg, 131.65 μmol). MS (ESI, m/z): 790 [M+H]+.
  • To a solution of Compound 2-10 (104 mg, 131.65 μmol) in CH3CN (3 mL) was added HCl (1 mL, 4 M in 1,4-dioxane). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched by saturated aqueous NaHCO3 solution (20 mL) and extracted with EA (2×30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 2-11 (109 mg, 146.12 μmol). MS (ESI, m/z): 746 [M+H]+.
  • To a solution of Compound 2-11 (109 mg, 146.12 μmol) in DMF (3 mL) was added CsF (0.40 g, 2.63 mmol). The reaction mixture was stirred at 40° C. for 16 hours. The mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with EA (2×20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 40% B in 36 min at a flow rate of 60 mL/min, 240 nm).
  • The acetonitrile in the eluent was concentrated. The resulting aqueous layer was added NaHCO3 (30 mL), extracted with EA (30 mL×2) and the organic layer was concentrated under reduced pressure to give Compound 2 (17.7 mg, 30.02 μmol). MS (ESI, m/z): 590 [M+H]+.
    • Example 3 5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 3 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01259
    Figure US20240376128A1-20241114-C01260
    Figure US20240376128A1-20241114-C01261
  • To a solution of Compound 3-1 (trans-tert-butyl(2-fluorocyclopropyl)carbamate, 601 mg, 3.43 mmol) in EA (10 mL) was added HCl (6 mL, 4 M in EA). The reaction mixture was stirred at room temperature overnight under nitrogen atmosphere and concentrated under reduced pressure to give Compound 3-2 (408 mg, crude, HCl salt). MS m/z: 117 [M+H+41]+.
  • To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.68 g, 2.69 mmol), DIEA (1.42 g, 10.99 mmol) in DCM (8 mL) was added Compound 3-2 (408 mg) at 0° C. The mixture was stirred at room temperature for 1 h, and then diluted with DCM (20 mL). The organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (MeOH:DCM=1:20, v/v) to give Compound 3-3 (413 mg, 1.42 mmol). MS m/z: 291/293 [M+H]+.
  • To a solution of Compound 3-3 (341 mg, 1.17 mmol), CH3I (692 mg, 4.88 mmol) in DMF (2 mL) was added NaH (71 mg, 1.78 mmol, 60% content). The mixture was stirred at room temperature for 4 h, quenched with saturated NH4Cl aqueous solution (2 mL), extracted with EA (30 mL) and washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (EA:Hex=2:1, v/v) to give Compound 3-4 (271 mg, 0.89 mmol). MS m/z: 305/307 [M+H]+.
  • A solution of Compound 3-4 (271 mg, 0.89 mmol), INT 2 (217 mg, 1.36 mmol) and KF (166 mg, 2.86 mmol) in DMSO (6 mL) was stirred at 90° C. for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and extracted with EA (30 mL). The organic layer was washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 3-5 (139 mg, 0.325 mmol). MS m/z: 428 [M+H]+.
  • To a solution of Compound 3-5 (139 mg, 0.325 mmol), INT 3 (253 mg, 0.494 mmol) in toluene (5 mL) and water (1 mL) was added Cs2CO3 (322 mg, 0.988 mmol) and cataCXium A Pd G3 (37 mg, 0.508 mmol). The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 3-6 as a brown solid (203 mg, 0.261 mmol). MS m/z: 778 [M+H]+.
  • A solution of Compound 3-6 (203 mg, 0.261 mmol) and HCl (4 M in 1,4-dioxane, 1 mL) in ACN (4 mL) was stirred at RT for 1 h. The solution was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 3-7 (crude, 210 mg, 0.286 mmol). MS m/z: 734 [M+H]+.
  • A solution of Compound 3-7 (210 mg, 0.286 mmol) and CsF (0.77 g, 5.07 mmol) in DMF (5 mL) was stirred at 40° C. for 2 h under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with EA (20 mL). The collected organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 45% B in 45 min at a flow rate of 60 mL/min, 235 nm) to give Compound 3 (TFA salt) containing Compound 3A (TFA salt) and Compound 3B (TFA salt) (118.3 mg, 0.171 mmol). MS m/z: 578 [M+H]+.
    • Example 4 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 3A (TFA salt)”) 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 3B (TFA salt)”)
  • Figure US20240376128A1-20241114-C01262
    Figure US20240376128A1-20241114-C01263
    Figure US20240376128A1-20241114-C01264
  • To a solution of Compound 3-1 (trans-ter-butyl (2-fluorocyclopropyl)-carbamate, 10 g, 5.8-ml) in for 4 h, and concentrated under reduced pressure to give an off white solid. The off white solid was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (14.41 g, 57.08 mmol) and DIEA (19.63 g, 151.89 mmol) in DCM (100 mL) at 0° C. The mixture was stirred at room temperature for 1 h and diluted with water (80 mL). The collected organic layer was washed with brine twice (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was stirred with Hex:EA=15:1 (160 ml) and filtered to give a brown solid (17.68 g, 60.74 mmol). The solid was separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRAL ART Cellulose-SC column (2 cm×25 cm, 5 m); mobile phase, Hex/EtOH (50:50, v/v); Flowing rate: 20 ml/min. This results in Compound 3A-3 (7.76 g, 26.66 mmol, the first eluting isomer, Retention Time 3.831 min) and Compound 3B-3 (6.95 g, 23.88 mmol, the second eluting isomer, Retention Time 5.243 min). MS m/z: 291/293 [M+H]+.
  • To a solution of Compound 3A-3 (244 mg, 0.84 mmol) and CH3I (507 mg, 3.57 mmol) in DMF (4 mL) was added NaH (45 mg, 1.13 mmol, 60% content). The mixture was stirred at room temperature for 22 h, quenched with water (30 mL), extracted with EA (30 mL), washed with brine twice (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 3A-4 (crude, 237 mg, 0.78 mmol). MS m/z: 305/307 [M+H]+.
  • To a solution of Compound 3A-4 (237 mg, 0.78 mmol) and INT 2 (145 mg, 0.91 mmol) in THF (5 mL) was added t-BuONa (98 mg, 1.02 mmol) in portions at −10° C. The mixture was stirred at −10° C. for 2.5 h. The mixture was quenched with water (30 mL) and extracted with EA (30 mL). The collected organic layer was washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 3A-5 (154 mg, 0.36 mmol). MS m/z: 428 [M+H]+.
  • To a mixture of Compound 3A-5 (154 mg, 0.36 mmol), INT 3 (228 mg, 0.44 mmol) in toluene (10 mL) and water (2.5 mL) were added Cs2CO3 (240 mg, 0.74 mmol) and cataCXium A Pd G3 (36 mg, 0.049 mmol). The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 3A-6 (186 mg, 0.24 mmol). MS m/z: 778 [M+H]+.
  • A solution of Compound 3A-6 (186 mg, 0.24 mmol) and HCl (4 M in dioxane, 1.5 mL) in ACN (4.5 mL) was stirred at RT for 1 h. The solution was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL). The collected organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 3A-7 (crude, 180 mg, 0.25 mmol). MS m/z: 734 [M+H]+.
  • A mixture of Compound 3A-7 (180 mg, 0.25 mmol) and CsF (0.51 g, 3.36 mmol) in DMF (5 mL) was stirred at 45° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL). The collected organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 43% B in 30 min at a flow rate of 60 mL/min, 230 nm) to give Compound 3A (TFA salt) (112.6 mg, 0.16 mmol). MS m/z: 578 [M+H]+.
  • 1H NMR (400 MHz, CD3OD) δ 9.58 (d, 1H), 7.97-7.83 (m, 1H), 7.46-7.32 (m, 2H), 7.26 (s, 1H), 5.58 (d, 1H), 4.96-4.65 (m, 3H), 4.20-3.75 (m, 4H), 3.59-3.36 (m, 5H), 2.81-2.52 (m, 2H), 2.51-2.28 (m, 3H), 2.19 (s, 1H), 1.78 (d, 1H), 1.48-1.26 (m, 1H).
  • To a solution of Compound 3B-3 (246 mg, 0.85 mmol) and CH3I (510 mg, 3.59 mmol) in DMF (4 mL) was added NaH (45 mg, 1.13 mmol, 60% content). The mixture was stirred at room temperature for 22 h, quenched with water (30 mL), extracted with EA (30 mL), washed with brine twice (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 3B-4 (crude, 271 mg, 0.89 mmol). MS m/z: 305/307 [M+H]+.
  • To a solution of Compound 3B-4 (271 mg, 0.89 mmol) and INT 2 (158 mg, 0.99 mmol) in THF (5 mL) was added t-BuONa (110 mg, 1.14 mmol) in portions at −10° C. The mixture was stirred at −10° C. for 2.5 h.
  • The mixture was quenched with water (30 ml) and extracted with EA (30 mL). The collected organic layer was washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 3B-5 (150 mg, 0.35 mmol). MS m/z: 428 [M+H]+.
  • To a solution of Compound 3B-5 (150 mg, 0.35 mmol), INT 3 (231 mg, 0.45 mmol) in toluene (10 mL) and water (2.5 mL) were added Cs2CO3 (250 mg, 0.77 mmol) and cataCXium A Pd G3 (39 mg, 0.053 mmol).
  • The reaction mixture was stirred at 100° C. for overnight under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 3B-6 (163 mg, 0.21 mmol). MS m/z: 778 [M+H]+.
  • A solution of Compound 3B-6 (163 mg, 0.21 mmol) and HCl (4 M in dioxane, 1.5 mL) in ACN (4.5 mL) was stirred at room temperature for 1 h. The solution was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL). The collected organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 3B-7 (crude, 151 mg, 0.21 mmol). MS m/z: 734 [M+H]+.
  • A solution of Compound 3B-7 (151 mg, 0.21 mmol) and CsF (0.77 g, 5.07 mmol) in DMF (5 mL) was stirred at 45° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL). The collected organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 43% B in 33 min at a flow rate of 60 mL/min, 230 n) to give Compound 3B (TFA salt) (89.9 mg, 0.13 mmol). MS m/z: 578 [M+H]+.
  • 1H NMR (400 MHz, CD3OD) δ 9.59 (d, 1H), 7.98-7.83 (m, 1H), 7.50-7.32 (m, 2H), 7.28 (s, 1H), 5.58 (d, 1H), 4.96-4.60 (m, 3H), 4.15-3.78 (m, 4H), 3.60-3.39 (m, 5H), 2.83-2.52 (m, 2H), 2.51-2.30 (m, 3H), 2.19 (s, 1H), 1.79 (d, 1H), 1.47-1.25 (m, 1H).
    • Example 5 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (“Compound 3A”)
  • Figure US20240376128A1-20241114-C01265
    Figure US20240376128A1-20241114-C01266
  • To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (INT-1, 2.09 g, 8.28 mmol) and DIEA (2.16 g, 16.71 mmol) in DCM (30 mL) was added (1S,2S)-2-fluorocyclopropan-1-amine hydrochloride (0.93 g, 8.33 mmol) at 0° C. The mixture was stirred at room temperature for 1 h, diluted with DCM (20 mL), washed with water (20 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 3A-3 (2.40 g, 8.25 mmol, 98.99% yield). MS m/z: 291/293 [M+H]+.
  • To a solution of Compound 3A-3 (2.57 g, 8.84 mmol) and CH3I (4.84 g, 34.10 mmol) in DMF (25 mL) was added NaH (0.44 g, 11.00 mmol, 60% content). The mixture was stirred at room temperature for 5 h, quenched with saturated NH4Cl (20 mL) aqueous solution, extracted with EA (100 mL) and washed with brine (50 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was slurried with (50 mL, EA:Hex=1:10, v/v) to give Compound 3A-4 (2.25 g, 6.64 mmol, 75.05% yield). MS m/z: 305/307 [M+H]+.
  • To a solution of Compound 3A-4 (2.25 g, 6.64 mmol) and INT 2 (1.17 g, 7.35 mmol) in THF (30 mL) was added t-BuONa (0.85 g, 8.84 mmol) portion wise at −10° C. under nitrogen atmosphere. The mixture was stirred for 2 h, warmed to room temperature and extracted with EA (50 mL). The organic layer was washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was slurried with (50 mL, Hex:EA=9:1, v/v) to give Compound 3A-5 (2.44 g, 5.70 mmol, 77.33% yield). MS m/z: 428 [M+H]+.
  • To a solution of Compound 3A-5 (2.44 g, 5.70 mmol) and INT 3 (3.78 g, 7.38 mmol) in 1,4-dioxane (30 mL) and water (3 mL) were added Cs2CO3 (4.71 g, 14.46 mmol) and cataCXium A Pd G3 (0.42 g, 0.577 mmol). The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=50:1 to 30:1, v/v) to give Compound 3A-6 (3.57 g, 4.59 mmol, 80.46% yield). MS m/z: 778 [M+H]+.
  • A solution of Compound 3A-6 (3.57 g, 4.59 mmol) and HCl (16 mL, 4 M in 1,4-dioxane) in ACN (45 mL) was stirred at room temperature for 1 h. The solution was diluted with saturated NaHCO3 aqueous solution (30 mL) and extracted with EA (100 mL). The collected organic layer was washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 3A-7 (crude, 3.57 g, 4.86 mmol, 106.00% yield). MS m/z: 734 [M+H]+.
  • A mixture of Compound 3A-7 (3.57 g, 4.86 mmol) and CsF (3.58 g, 23.57 mmol) in DMF (35 mL) was stirred at 40° C. for 2 h under nitrogen atmosphere. The solution was diluted with water (50 mL) and extracted with EA (100 mL). The collected organic layer was washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was slurried with ACN (12 mL) to give Compound 3A (2.05 g, 3.55 mmol, 73.01% yield). MS m/z: 578 [M+H]+.
  • 1H NMR (400 MHz, CD3OD) δ 9.58 (d, 1H), 7.97-7.83 (m, 1H), 7.46-7.32 (m, 2H), 7.26 (s, 1H), 5.58 (d, 1H), 4.96-4.65 (m, 3H), 4.20-3.75 (m, 4H), 3.59-3.36 (m, 5H), 2.81-2.52 (m, 2H), 2.51-2.28 (m, 3H), 2.19 (s, 1H), 1.78 (d, 1H), 1.48-1.26 (m, 1H).
    • Example 6 4-(4-(cyclopropyl(methyl-d3)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (“Compound 4”)
  • Figure US20240376128A1-20241114-C01267
    Figure US20240376128A1-20241114-C01268
  • NaH (0.92 g, 38.3370 mmol) was added into a solution of Compound 4-1 (3.09 g, 19.6553 mmol) in DMF (30 mL) at 0° C., stirred for 30 mins and then trideuterio(iodo)methane (3.37 g, 23.2483 mmol) was dropped into the system at 0° C. The solution was stirred at room temperature for 2 hours, quenched with water (30 mL) at room temperature, extracted with EA (30 mL×2). The organic layer was washed with NaCl aqueous solution (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuum to give Compound 4-2 (3.71 g, 21.2907 mmol). MS m/z: 175 [M+H]+.
  • A solution of Compound 4-2 (3.71 g, 21.2906 mmol) and hydrogen chloride (4 M in dixoane, 10 mL) in DCM (10 mL) was stirred at room temperature for 2 h. then, more hydrogen chloride (4 M in dixoane, 10 mL) was added, and stirred at room temperature for 2 h. The solution was concentrated in vacuum to give Compound 4-3 (2.89 g, 26.1302 mmol). MS m/z: 75 [M+H]+.
  • Compound 4-3 (2.78 g, 25.1356 mmol) was dropped into the solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.88 g, 19.3298 mmol) and N,N-diisopropylethylamine (7.56 g, 58.4947 mmol) in DCM (20 mL) at 0° C., then the solution was stirred at room temperature for 14 h. The solution was diluted with 10% citric acid aqueous solution (100 mL), then the organic layer was washed with NaCl aqueous solution (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was slurried in 36 mL (EA:HEX=1:5) to give Compound 4-4 (5.27 g, 18.1637 mmol). MS m/z: 290 [M+H]+.
  • A solution of Compound 4-4 (5.27 g, 18.1637 mmol), INT 2 (4.33 g, 27.1984 mmol) and KF (3.29 g, 56.6297 mmol) in DMSO (150 mL) was stirred at 100° C. for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with water (200 mL) and extracted with EA (200 mL). The organic layer was filtered and the filter cake was collected to give Compound 4-5 (2.79 g, 6.7574 mmol). MS m/z: 413 [M+H]+.
  • A solution of Compound 4-5 (2.73 g, 6.6121 mmol), INT 3 (5.23 g, 10.2042 mmol), cataCXium A Pd G3 (0.51 g, 700.2897 μmol) and cesium carbonate (6.69 g, 20.5329 mmol) in toluene (150 mL) and water (30 mL) was stirred at 100° C. for 20 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated NaHCO3 aqueous solution (150 mL) and extracted with EA (150 mL). The organic layer was washed with aqueous NaCl solution (150 mL), then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica column to give Compound 4-6 (3.91 g, 5.1246 mmol). MS m/z: 763 [M+H]+.
  • A solution of Compound 4-6 (3.91 g, 5.1246 mmol) and hydrogen chloride (4 M in dixoane, 15 mL) in DCM (50 mL) was stirred at room temperature for 4 h. The solution was diluted with 10% NaHCO3 aqueous solution (20 mL) and extracted with DCM (20 mL). The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 4-7 (4.47 g, 6.2175 mmol). MS m/z: 719 [M+H]+.
  • A solution of Compound 4-7 (5.75 g, 7.9979 mmol) and CsF (5.05 g, 33.2448 mmol) in DMF (100 mL) was stirred for 20 hours at 40° C. under nitrogen atmosphere. The solution was diluted with water (150 mL) and extracted with EA (150 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was slurried with EA/Hex (15 mL/45 mL) to give Compound 4 (3.29 g, 5.8479 mmol). MS m/z: 563 [M+H]+.
  • 1H NMR (400 MHz, CD3OD) δ 9.59 (s, 1H), 7.90-7.82 (m, 1H), 7.37-7.27 (m, 2H), 7.22 (d, J=2.4 Hz, 1H), 5.45-5.27 (m, 1H), 4.45-4.29 (m, 2H), 3.61-3.54 (m, 1H), 3.53-3.34 (m, 4H), 3.16-3.07 (m, 1H), 2.47-2.24 (m, 2H), 2.18 (d, J=8.5 Hz, 1H), 2.13-2.01 (m, 2H), 1.95 (dd, J=14.4, 7.4 Hz, 1H), 1.29 (s, 1H), 1.16 (d, J=6.7 Hz, 2H), 0.98-0.81 (m, 2H).
    • Example 7 5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (“Compound 5”)
  • Figure US20240376128A1-20241114-C01269
    Figure US20240376128A1-20241114-C01270
  • A solution of Compound 3-4 (165 mg, 540.7877 μmol), ((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (99 mg, 578.1491 μmol) and KF (148 mg, 2.5475 mmol) in DMSO (5 mL) was stirred at 90° C. for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL×2). The organic layer was washed with NaCl aqueous solution, then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 5-2 (123 mg, 279.6181 μmol, 51.7075% yield). MS: m/z: 440 [M+H]+.
  • A solution of Compound 5-2 (123 mg, 279.6179 μmol), toluene (5 mL), INT 3 (224 mg, 437.0437 μmol), cataCXium A Pd G3 (42 mg, 57.6709 μmol), cesium carbonate (300 mg, 920.7569 μmol) and water (1 mL) was stirred at 100° C. for 18 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with water (30 mL) and extracted with EA (2×30 mL). The organic layer was washed with NaCl aqueous solution, then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 5-3 (149 mg, 188.6080 μmol, 67.4520% yield). MS: m/z: 790 [M+H]+.
  • A solution of Compound 5-3 (48 mg, 60.7596 μmol) and HCl (4 M in 1,4-dioxane, 0.8 mL) in DCM (4 mL) was stirred at room temperature for 0.5 h. The solution was diluted with 10% NaHCO3 aqueous solution (20 mL) and extracted with DCM (40 mL×2). The organic layer was washed with NaCl aqueous solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 5-4 (42 mg, 56.3043 mol, 92.6674% yield). MS: m/z: 746 [M+H]+.
  • A solution of Compound 5-4 (42 mg, 56.3043 μmol) and CsF (89 mg, 589.8987 μmol) in DMF (4 mL) was stirred for 6 hours at 35° C. under nitrogen atmosphere. The solution was diluted with water (30 mL) and extracted with EA (30 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 35% B in 37 min at a flow rate of 60 mL/min, 240 nm). The mixture was adjusted to pH 8-9 with saturated NaHCO3 and concentrated in vacuum. The aqueous layer was extracted with EA, the organic layer was washed with water twice, concentrated in vacuum to freeze-dried to give Compound 5 (16 mg). MS: m/z: 590 [M+H]+.
    • Example 8 4-(4-(ethyl(trans-2-fluorocyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 6 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01271
    Figure US20240376128A1-20241114-C01272
    Figure US20240376128A1-20241114-C01273
  • To a solution of Compound 3-3 (704 mg, 2.42 mmol) and iodoethane (1672 mg, 10.72 mmol) in DMF (10 mL) was added NaH (124 mg, 3.10 mmol, 60%). The mixture was stirred at room temperature for 24 h, then quenched with water (30 mL), extracted with EA (30 mL), washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 6-1 (45 mg, 0.14 mmol). MS m/z: 319/321[M+H]+.
  • A solution of Compound 6-1 (45 mg, 0.14 mmol), INT 2 (38 mg, 0.24 mmol) and KF (28 mg, 0.48 mmol) in DMSO (4 mL) was stirred at 95° C. for 19 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with water (30 mL) and extracted with EA (30 mL×2). The combined organic layers were washed with brine (40 mL), then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 6-2 (37 mg, 0.084 mmol). MS m/z: 442 [M+H]+.
  • To a solution of Compound 6-2 (37 mg, 0.084 mmol) and INT 3 (60 mg, 0.12 mmol) in toluene (4 mL) and water (1 mL) were added Cs2CO3 (61 mg, 0.19 mmol) and cataCXium A Pd G3 (25 mg, 0.034 mmol). The reaction mixture was stirred at 100° C. for 12 h under nitrogen atmosphere. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 6-3 (50 mg, 0.063 mmol). MS m/z: 792 [M+H]+.
  • A solution of Compound 6-3 (50 mg, 0.063 mmol) and HCl (4 M in 1,4-dioxane, 1 mL) in ACN (3 mL) was stirred at room temperature for 1 h. The solution was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 6-4 (crude, 56 mg, 0.075 mmol). MS m/z: 748 [M+H]+.
  • A solution of Compound 6-4 (56 mg, 0.075 mmol) and CsF (0.34 g, 2.24 mmol) in DMF (5 mL) was stirred at 45° C. for 4 h. The mixture was diluted with water (30 mL) and extracted with EA (30 mL). The collected organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 44% B in 40 min at a flow rate of 40 mL/min, 235 nm) to give Compound 6 (TFA salt) (10.7 mg, 0.015 mmol). MS m/z: 592 [M+H]+.
    • Example 9 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl-d3)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 7 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01274
    Figure US20240376128A1-20241114-C01275
  • A solution of Compound 3A-3 (478 mg, 1.64 mmol) and CD3I (1024 mg, 7.06 mmol) in DMF (8 mL) was added NaH (90 mg, 2.25 mmol, 60%). Then the mixture was stirred at room temperature for 5 h. The solution was quenched with saturated NH4Cl aqueous solution (2 mL), extracted with EA (30 mL), washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC (EA:Hex=1:3, v/v) to give Compound 7-1 (394 mg, 1.28 mmol, 77.87% yield). MS m/z: 308/310 [M+H]+.
  • A solution of Compound 7-1 (394 mg, 1.28 mmol) and INT 2 (207 mg, 1.30 mmol) in THF (7 mL) was added t-BuONa (149 mg, 1.55 mmol) portion wise at −10° C. under nitrogen atmosphere and then the mixture was stirred for 2 h, allowed to cool to room temperature and extracted with EA (30 mL). The organic layer was washed with brine (30 mL×2), then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 7-2 (358 mg, 0.831 mmol, 64.98% yield). MS m/z: 431 [M+H]+.
  • To a solution of Compound 7-2 (358 mg, 0.831 mmol) and INT 3 (523 mg, 1.02 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was added Cs2CO3 (710 mg, 2.18 mmol) and cataCXium A Pd G3 (72 mg, 0.099 mmol). The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated under vacuum. The residue was purified by Pre-TLC (DCM:MeOH=15:1, v/v) to give Compound 7-3 as a brown solid: (484 mg, 0.620 mmol, 74.59% yield). MS m/z: 781 [M+H]+.
  • A solution of Compound 7-3 (484 mg, 0.620 mmol) and HCl (4 M in 1,4-dioxane, 1.5 mL) in ACN (6 mL) was stirred at room temperature for 2 h. The solution was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 7-4 (490 mg, 0.665 mmol, 107.29% yield). MS m/z: 737 [M+H]+.
  • A solution of Compound 7-4 (490 mg, 0.665 mmol) and CsF (0.82 g, 5.40 mmol) in DMF (6 mL) was stirred at 40° C. for 2 h under nitrogen atmosphere. The solution was diluted with water (10 mL) and extracted with EA (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 20% B to 46% B in 35 min at a flow rate of 70 mL/min, 240 nm) to freeze-dried to give Compound 7 (TFA salt) (220.5 mg, 0.380 mmol, 57.12% yield). MS m/z: 581 [M+H]+.
    • Example 10 4-(4-(cyclopropyl(methyl-d3)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl methylcarbamate (“Compound 8”)
  • Figure US20240376128A1-20241114-C01276
  • To a solution of Compound 4 (2.44 g, 4.34 mmol) and DIEA (8 ml) in DCM (150 mL) was added methylcarbamic chloride (1.20 g, 12.83 mmol). The reaction mixture was stirred at 30° C. for 4 hours. The reaction mixture was diluted with NH4Cl aqueous solution (80 mL) and extracted with DCM (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by Pre-HPLC-Gilson with the following conditions: Column, CHIRAL ART Cellulose SA column (2 cm×25 cm, 5 μm) mobile phase, Hex/EtOH (50:50); Flowing rate: 20 mL/min to give Compound 8 (1.668 g, 2.69 mmol). MS m/z: 620 [M+H]+.
    • Example 11 (2R,7aS)-7a-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol 2,2,2-trifluoroacetic acid (“Compound 9 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01277
    Figure US20240376128A1-20241114-C01278
  • A solution of Compound 5 (77 mg, 97.4685 μmol) in DCM (5 mL) was stirred at 5° C. under nitrogen atmosphere. A solution of BBr3 (77 mg, 307.3570 μmol) in DCM (1 mL) was added to the mixture dropwise. The mixture was stirred for 48 h at room temperature, diluted with saturated NaHCO3 (20 mL) aqueous solution and extracted with DCM (2×30 mL). The organic layer was washed with NaCl aqueous solution, then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 9-1 (19 mg, 24.4854 μmol, 25.1214% yield). MS: m/z: 732 [M+H]+.
  • A solution of Compound 9-1 (19 mg, 25.9591 μmol) and CsF (125 mg, 822.8914 μmol) in DMF (4 mL) was stirred for 3 hours at 35° C. under nitrogen atmosphere. The solution was diluted with water (30 mL) and extracted with EA (30 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 40% B in 28 min at a flow rate of 40 mL/min, 234 nm) to freeze-dried to give Compound 9 (TFA salt) (1.8 mg). MS: m/z: 576 [M+H]+.
    • Example 12 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (“Compound 10”)
  • Figure US20240376128A1-20241114-C01279
    Figure US20240376128A1-20241114-C01280
  • A solution of INT 1 (280 mg, 1.1091 mmol), 1-methylcyclopropylamine hydrochloride (110 mg, 1.0225 mmol) and DIEA (474 mg, 3.6675 mmol) in DCM (5 mL) was stirred at room temperature for 2 h. The solution was diluted with 10% NaHCO3 aqueous solution (10 mL) and extracted with DCM (20 mL×2). The organic layer was washed with NaCl aqueous solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give Compound 10-1 (378 mg, crude). MS: m/z: 287 [M+H]+.
  • A solution of Compound 10-1 (378 mg, 1.3165 mmol), INT 2 (219 mg, 1.3756 mmol) and KF (364 mg, 6.2654 mmol) in DMSO (5 mL) was stirred at 90° C. for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (40 mL×2). The organic layer was washed with NaCl aqueous solution (20 mL), then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 10-2 (307 mg, 749.0366 μmol, 56.8951% yield). MS: m/z: 410 [M+H]+.
  • A solution of Compound 10-2 (146 mg, 356.2194 μmol), toluene (5 mL), INT-3 (241 mg, 470.2122 mol), cataCXium A Pd G3 (38 mg, 52.1785 μmol), cesium carbonate (348 mg, 1.0681 mmol) and water (1 mL) was stirred at 100° C. for 18 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with EA (25 mL×2). The organic layer was washed with NaCl aqueous solution (10 mL), then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 10-3 (184 mg, 242.1140 μmol, 67.9677% yield). MS: m/z: 760 [M+H]+.
  • A solution of Compound 10-3 (184 mg, 242.1140 μmol) and HCl (4 M in 1,4-dioxane, 1 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10% NaHCO3 aqueous solution (10 mL) and extracted with DCM (30 mL). The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 10-4 (172 mg, 240.2503 μmol, 99.2303% yield). MS: m/z: 716 [M+H]+.
  • A solution of Compound 10-4 (172 mg, 240.2503 μmol) and CsF (179 mg, 1.1784 mmol) in DMF (5 mL) was stirred for 20 hours at 35° C. under nitrogen atmosphere. The solution was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with EA (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 52% B in 37 min at a flow rate of 70 mL/min, 240 nm). The mixture was adjusted to pH=8 with saturated NaHCO3 and concentrated in vacuum. The aqueous layer was extracted with EA, the organic layer was washed with water twice, concentrated in vacuum to freeze-dried to give Compound 10 (TFA salt) (54 mg). MS: m/z: 560 [M+H]+.
    • Example 13 4-(4-((2,2-difluorocyclopropyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 11 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01281
    Figure US20240376128A1-20241114-C01282
  • A mixture of 2,2-difluorocyclopropane-1-carboxylic acid (4.95 g, 40.55 mmol), DPPA (13.73 g, 49.89 mmol) and TEA (4.82 g, 47.70 mmol) in t-BuOH (30 mL) was stirred at 90° C. for 16.5 h. The reaction mixture was concentrated under reduced pressure and diluted with water (40 mL) and EA (40 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Hex:EA=10:1, v/v) to give Compound 11-1 (7.34 g, 93.69%).
  • A solution of Compound 11-1 (1.97 g, 10.20 mmol) and HCl (4 M in 1,4-dioxane, 5 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give Compound 11-2 (crude). Compound 11-2 (crude) was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.36 g, 5.39 mmol) and DIEA (2.70 g, 20.89 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 17 h, then diluted with water (10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Hex:EA=2:1, v/v) to give Compound 11-3 (1.18 g, 70.87%). MS m/z: 309/311 [M+H]+.
  • To a solution of Compound 11-3 (0.59 g, 1.91 mmol) and CH3I (0.61 g, 4.30 mmol) in DMF (5 mL) was added NaH (0.11 g, 2.75 mmol, 60% content). The mixture was stirred at room temperature for 17 h, quenched with water (20 mL), extracted with EA (30 mL×2) and concentrated under reduced pressure. The residue was purified by Pre-TLC (EA:Hex=1:1, v/v) to give Compound 11-4 (0.13 g, 21.07%). MS m/z: 323/325 [M+H]+.
  • A mixture of Compound 11-4 (0.13 g, 0.40 mmol), INT 2 (156 mg, 0.98 mmol) and KF (125 mg, 2.15 mmol) in DMSO (3 mL) was stirred at 90° C. for 5 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (20 mL) and EA (20 mL). The collected organic layer was washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=11:1, v/v) to give Compound 11-5 (153 mg, 85.29%). MS m/z: 446 [M+H]+.
  • To a solution of Compound 11-5 (153 mg, 0.34 mmol) and INT 3 (263 mg, 0.51 mmol) in toluene (5 mL) and water (1 mL) were added Cs2CO3 (228 mg, 0.70 mmol) and cataCXium A Pd G3 (40 mg, 0.05 mmol). The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (10 mL) and EA (10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=10:1, v/v) to give Compound 11-6 (174 mg, 63.70%). MS m/z: 796 [M+H]+.
  • A solution of Compound 11-6 (174 mg, 0.22 mmol) and HCl (4 M in 1,4-dioxane, 2 mL) in DCM (10 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and EA (10 mL) and the pH was adjusted to 9 with K2CO3. The collected organic layer was concentrated under reduced pressure to give Compound 11-7 (crude). MS m/z: 752 [M+H]+.
  • A mixture of Compound 11-7 (crude) and CsF (0.57 g, 3.75 mmol) in DMF (5 mL) was stirred at room temperature for 18 h under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 50% B in 46 min at a flow rate of 60 mL/min, 230 nm) to give freeze-dried Compound 11 (TFA salt) (44.8 mg). MS m/z: 596 [M+H]+.
    • Example 14 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2R)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 12 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01283
    Figure US20240376128A1-20241114-C01284
  • A mixture of (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (4.16 g, 39.97 mmol), DPPA (12.21 g, 47.97 mmol) and TEA (4.91 g, 48.52 mmol) in t-BuOH (45 mL) was stirred at 90° C. for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with water (40 mL) and EA (40 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Hex:EA=10:1, v/v) to give Compound 12-1 (7.04 g, 100.53%).
  • To a solution of Compound 12-1 (1.31 g, 7.48 mmol) and CH3I (1.3 g, 9.16 mmol) in DMF (10 mL) was added NaH (0.35 g, 8.75 mmol, 60% content). The mixture was stirred at room temperature for 25 h, quenched with water (30 mL), extracted with EA (30 mL), washed with brine (30 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (EA:Hex=1:10, v/v) to give Compound 12-2 (0.66 g, 46.65%). MS m/z: 134 [M+H−56]+.
  • A solution of Compound 12-2 (0.66 g, 3.49 mmol) and HCl (4 M in dioxane, 2 mL) in DCM (10 mL) was stirred at room temperature for 17.5 h. The solution was concentrated under reduced pressure to give Compound 12-3 (crude). Compound 12-3 (crude) was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (600 mg, 2.38 mmol) and DIEA (1 g, 7.74 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 h and diluted with water (10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by Pre-TLC (Hex:EA=1:1, v/v) to give Compound 12-4 (0.18 g, 16.96%). MS m/z: 305/307 [M+H]+.
  • A mixture of Compound 12-4 (0.18 g, 0.59 mmol), INT 2 (234 mg, 1.47 mmol) and KF (187 mg, 3.22 mmol) in DMSU (5 mL) was stirred at 90° C. for 3.5 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (10 mL) and EA (10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=10:1, v/v) to give Compound 12-5 (212 mg, 83.99%). MS m/z: 428 [M+H]+.
  • To a solution of Compound 12-5 (212 mg, 0.50 mmol), INT 3 (337 mg, 0.66 mmol) in toluene (5 mL) and water (1 mL) was added Cs2CO3 (407 mg, 1.25 mmol) and cataCXium A Pd G3 (36 mg, 0.05 mmol). The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (10 mL) and EA (10 mL). The organic layer was collected and concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=12:1, v/v) to give Compound 12-6 (227 mg, 58.89%). MS m/z: 778 [M+H]+.
  • A solution of Compound 12-6 (227 mg, 0.29 mmol) and HCl (4 M in 1,4-dioxane, 2 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (10 mL) and EA (10 mL) and the pH was adjusted to 9 with K2CO3. The organic layer was collected and concentrated under reduced pressure to give Compound 12-7 (crude). MS m/z: 734 [M+H]+.
  • A mixture of Compound 12-7 (crude) and CsF (0.82 g, 5.40 mmol) in DMF (5 mL) was stirred at room temperature for 1.5 h under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 32% B in 32 min at a flow rate of 60 mL/min, 230 nm) to give freeze-dried Compound 12 (TFA salt) (89.6 mg). MS m/z: 578 [M+H]+.
    • Example 15
  • 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1R,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
  • Figure US20240376128A1-20241114-C01285
    Figure US20240376128A1-20241114-C01286
  • SM (488 mg, 1.97 mmol) was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (491 mg, 1.94 mmol) and DIEA (0.72 g, 5.57 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 0.2 h and diluted with DCM (30 mL). The reaction mixture was washed with water (50 mL) and concentrated under reduced pressure. The residue was added to a solution of EA (3 mL) and Hexane (10 mL), stirred for 1.5 h and filtered to give Compound 13-1 (0.52 g, 91.85%). MS m/z: 291/293 [M+H]+.
  • To a solution of Compound 13-1 (491 mg, 1.69 mmol) and CH3I (965 mg, 6.80 mmol) in DMF (8 mL) was added NaH (132 mg, 5.5 mmol, 60% content). The mixture was stirred at room temperature for 3.5 h, quenched with water (20 mL), extracted with EA (20 mL×2) and concentrated under reduced pressure to give Compound 13-2 (0.54 g, 104.92%). MS m/z: 305/307 [M+H]+.
  • A mixture of Compound 13-2 (0.27 g, 0.88 mmol), INT 2 (268 mg, 1.68 mmol) and KF (304 mg, 5.23 mmol) in DMSO (3 mL) were stirred at 90° C. for 3.5 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (20 mL) and EA (20 mL). The organic layer was washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by Pre-TLC (EA) to give Compound 13-3 (91 mg, 24.03%). MS m/z: 428 [M+H]+.
  • To a solution of Compound 13-3 (91 mg, 0.21 mmol) and INT 3 (159 mg, 0.31 mmol) in toluene (5 mL) and water (1 mL) were added Cs2CO3 (225 mg, 0.69 mmol) and cataCXium A Pd G3 (44 mg, 0.06 mmol). The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with water (10 mL) and EA (10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=10:1, v/v) to give Compound 13-4 (70 mg, 42.30%). MS m/z: 778 [M+H]+.
  • A solution of Compound 13-4 (70 mg, 0.09 mmol) and HCl (4 M in dioxane, 2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (10 mL) and EA (10 mL) and the pH was adjusted to 9 with K2CO3. The collected organic layer was concentrated under reduced pressure to give Compound 13-5 (crude). MS m/z: 734 [M+H]+.
  • A solution of Compound 13-5 (crude) and CsF (0.28 g, 1.84 mmol) in DMF (2 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 36% B in 35 min at a flow rate of 60 mL/min, 230 nm) to give freeze-dried Compound 13 (TFA salt) (28.8 mg). MS m/z: 578 [M+H]+.
    • Example 16 4-(4-(cyclopropyl(cyclopropylmethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Figure US20240376128A1-20241114-C01287
    Figure US20240376128A1-20241114-C01288
  • To a solution of Compound 14-1 (407 mg, 1.49 mmol) and (bromomethyl)cyclopropane (618 mg, 4.58 mmol) in ACN (8 mL) was added Cs2CO3 (1.07 g, 3.30 mmol). The mixture was stirred at 80° C. overnight, quenched with saturated NH4Cl aqueous solution (2 mL) and extracted with EA (30 mL). The organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (EA:Hex=1:3, v/v) to give Compound 14-2 (133 mg, 0.406 mmol, 27.28% yield). MS m/z: 327/329 [M+H]+.
  • To a solution of Compound 14-2 (133 mg, 0.406 mmol) and INT 2 (102 mg, 0.641 mmol) in DMSO (5 mL) was added KF (71 mg, 1.22 mmol). The reaction was stirred at 98° C. overnight under nitrogen atmosphere. The mixture was allowed to cool to room temperature and extracted with EA (30 mL). The organic layer was washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=20:1, v/v) to give Compound 14-3 (123 mg, 0.273 mmol, 67.25% yield). MS m/z: 450 [M+H]+.
  • To a solution of Compound 14-3 (123 mg, 0.273 mmol) and INT 3 (175 mg, 0.341 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was added Cs2CO3 (243 mg, 0.746 mmol) and cataCXium A Pd G3 (27 mg, 0.037 mmol). The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM:MeOH=20:1, v/v) to give Compound 14-4 as a brown solid (118 mg, 0.147 mmol, 53.95% yield). MS m/z: 800 [M+H]+.
  • To a solution of Compound 14-4 (78 mg, 0.097 mmol) and HCl (4 M in 1,4-dioxane, 1 mL) in ACN (4 mL) was stirred at room temperature for 2 h. The solution was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude Compound 14-5 (65 mg, 0.086 mmol, 88.19% yield). MS m/z: 756 [M+H]+.
  • A mixture of Compound 14-5 (65 mg, 0.086 mmol) and CsF (155 mg, 1.02 mmol) in DMF (3 mL) was stirred at 40° C. for 2 h under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with EA (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 20% B to 46% B in 35 min at a flow rate of 70 mL/min, 240 nm) to give freeze-dried Compound 14 (TFA salt) (34.5 mg, 0.048 mmol, 56.22% yield). MS m/z: 600 [M+H]+.
    • Example 17 5-ethyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 15 (TFA salt)”) 6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-vinylnaphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 16 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01289
  • To a solution of Compound 3 (208 mg, 0.360 mmol) in MeOH (8 mL) was added Pd/C (84 mg, 0.079 mmol, 10% wt) under hydrogen atmosphere. The reaction was stirred for 4 h at room temperature. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 46% B in 45 min at a flow rate of 60 mL/min, 230 nm) to give freeze-dried Compound 15 (TFA salt) (148.9 mg, 0.214 mmol, 59.44% yield), MS m/z: 582 [M+H]+ and Compound 16 (TFA salt) (31.7 mg, 0.046 mmol, 12.69% yield), MS m/z: 580 [M+H]+.
    • Example 18 4-(4-(cyclopropyl(2,2-difluoroethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 17 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01290
  • To a solution of tert-butyl cyclopropylcarbamate (2.70 g, 17.17 mmol) in DMF (35 mL) was added NaH (1.26 g, 31.50 mmol, 60% content) at −10° C. After stirring for 0.5 h, 1,1-difluoro-2-iodoethane (4.5 g, 23.44 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 16 h, quenched with water (80 mL), extracted with EA (50 mL), washed with brine (50 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column to give Compound 17-1 (360 mg, 1.63 mmol). MS m/z: 222 [M+H]+.
  • To a solution of Compound 17-1 (360 mg, 1.63 mmol) in ACN (9 mL) was added HCl (3 mL, 4 M in dioxane). The reaction mixture was stirred at room temperature for 1.5 h and concentrated under reduced pressure to give an off white solid. The solid was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (479 mg, 1.90 mmol) and DIEA (935 mg, 7.23 mmol) in ACN (10 mL). The mixture was stirred at 50° C. for 2 h, diluted with water (30 mL) and extracted with EA (30 mL×2). The organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 17-2 (179 mg, 0.53 mmol). MS m/z: 337 [M+H]+.
  • A mixture of Compound 17-2 (179 mg, 0.53 mmol), INT 2 (135 mg, 0.85 mmol) and KF (100 mg, 1.72 mmol) in DMSO (10 mL) was stirred at 95° C. for 17 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with water (30 mL) and extracted with EA (2×30 mL). The organic layer was washed with NaCl aqueous solution (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 17-3 (128 mg, 278.34 μmol). MS: m/z: 460 [M+H]+.
  • To a solution of Compound 17-3 (121 mg, 0.26 mmol) and INT 3 (179 mg, 0.35 mmol) in toluene (6 mL) and water (1.5 mL) were added Cs2CO3 (177 mg, 0.54 mmol) and cataCXium A Pd G3 (39 mg, 0.054 mmol).
  • The reaction mixture was stirred at 100° C. overnight under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with water (30 mL) and extracted with EA (2×30 mL). The organic layers were combined, washed with NaCl aqueous solution (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 17-4 (140 mg, 0.17 mmol). MS m/z: 810 [M+H]+.
  • A solution of Compound 17-4 (140 mg, 172.84 μmol) and HCl (4 M in 1,4-dioxane, 1.5 mL) in ACN (4.5 mL) was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure, diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (30 mL×2). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 17-5 (crude, 136 mg, 177.56 μmol). MS m/z: 766 [M+H]+.
  • A mixture of Compound 17-5 (136 mg, 177.56 μmol) and CsF (0.37 g, 2.44 mmol) in DMF (5 mL) was stirred at 40° C. for 2 h. The mixture was diluted with water (30 mL) and extracted with EA (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 43% B in 30 min at a flow rate of 60 mL/min, 230 nm) to give freeze-dried Compound 17 (TFA salt) (66.9 mg, 92.45 μmol). MS m/z: 610 [M+H]+.
    • Example 19 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formic acid (“Compound 18 (HCOOH salt)”)
  • Figure US20240376128A1-20241114-C01291
    Figure US20240376128A1-20241114-C01292
  • To a solution of INT 1 (200 mg, 0.80 mmol) in DCM (4 mL) was added DIEA (692 mg, 5.34 mmol) at room temperature. The mixture was cooled to −40° C. under argon atmosphere and cyclopropanamine (46 mg, 0.80 mmol) in DCM (0.5 mL) was added dropwise. After that the reaction mixture was stirred for 1 h at −40° C.
  • Then the reaction mixture was quenched with water (4 mL) and extracted with DCM (8 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give Compound 18-1 (220 mg, crude) as a yellow solid. MS m/z: 273[M+H]+.
  • To a solution of Compound 18-1 (270 mg crude, 0.99 mmol) and INT 2 (315 mg, 1.98 mmol) in 1,4-dioxane (5 mL) was added DIEA (385 mg, 2.91 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 80° C. and stirred overnight. After that, the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL×3). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with Petroleum ether/EtOAc=1:1) to give Compound 18-2 (200 mg, yield 63.8% for two steps) as a yellow solid. MS m/z: 396 [M+H]+.
  • Compound 18-2 (150 mg, 0.38 mmol), INT 3 (300 mg, 0.57 mmol), Cs2CO3 (369 mg, 1.14 mmol) and Pd(dppf)Cl2 (84 mg, 0.11 mmol) were added successively into toluene/water=3:1 (3 mL), degassing the reaction with argon for 10 min. The mixture was heated to 100° C. under argon atmosphere and stirred for 12 h. After that, the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with water (5 mL), brine (5 mL), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10:1) to give Compound 18-3 (50 mg, yield 17.7%) as a yellow solid. MS m/z: 746 [M+H]+.
  • To a solution of Compound 18-3 (50 mg, 0.07 mmol) in DCM (2 mL) was added HCl (4 M in 1,4-dioxane, 0.4 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give Compound 18-4 (50 mg, crude) as a yellow solid. MS m/z: 702 [M+H]+.
  • To a solution of Compound 18-4 (50 mg crude, 0.07 mmol) in DMF (1 mL) was added CsF (162 mg, 1.07 mmol) at room temperature. The reaction mixture was heated to 40° C. and stirred for 12 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 18 (HCOOH salt, 3.5 mg, yield 8.8% for two steps) as a yellow solid.
  • 1H NMR (400 MHz, CD3OD): δ 9.15 (s, 1H), 8.44 (brs, 1H), 7.87 (s, 1H), 7.36-7.30 (m, 2H), 7.20 (s, 1H), 5.56-5.43 (m, 1H), 4.66-4.62 (m, 2H), 3.89-3.65 (m, 3H), 3.62 (s, 2H), 3.20 (s, 1H), 2.54-2.49 (m, 2H), 2.36-2.25 (m, 4H), 0.98-0.97 (m, 2H), 0.82 (s, 2H). MS m/z: 546 [M+H]+.
    • Example 20 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methyl(1-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-1 naphthalen-2-ol (“Compound 19”)
  • Figure US20240376128A1-20241114-C01293
  • NaH (112 mg, 2.8 mmol) was added to a DMF solution of Compound 19-1 (400 mg, 2.34 mmol) at 0° C. under N2 atmosphere. The mixture was stirred for 1 h. After that, the mixture was added Mel (400 mg, 2.8 mmol) and stirred overnight. After the completion of reaction, the mixture was poured into water (5 mL) and extracted with EtOAc (5 mL). The organic layer was washed with water (5 mL), brine (5 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness. The residue was purified by column (eluted with Petroleum ether/EtOAc=3:1) to give Compound 19-2 (400 mg, yield 92.5%).
  • 1H NMR (300 MHz, CDCl3): δ 1.43 (s, 9H), 1.33 (s, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 2H), 0.56 (s, 2H).
  • To a solution of Compound 19-2 (400 mg, 2.1 mmol) in DCM (2.0 mL) was added HCl/dioxane (2.0 mL) at room temperature. The mixture was stirred for 2 h. Then the reaction mixture was concentrated to give Compound 19-3 (150 mg, crude).
  • 1H NMR (300 MHz, CDCl3): δ 1.42 (s, 3H), 1.12 (s, 3H), 0.83-0.75 (m, 2H), 0.63 (t, J=6.0 Hz, 2H).
  • Compound 19-3 (300 mg, 1.20 mmol) and DIEA (1.0 g, 7.9 mmol) were added successively into DCM (5 mL) under N2 atmosphere. The mixture was cooled to −40° C. and INT 1 (114 mg, 1.34 mmol) was added. The resulting mixture was stirred for 1 h. After that, the mixture was poured into water (5 mL) and extracted with DCM (5 mL). The organic layer was washed with water (5 mL), brine (5 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with Petroleum ether/EtOAc=3:1) to give Compound 19-4 (200 mg, yield 55.8%). MS m/z: 301 [M+H]+.
  • Compound 19-4 (200 mg, 0.66 mmol), INT 2 (211 mg, 1.32 mmol), DIEA (260 mg, 1.9 mmol) and 4A MS were added successively into dioxane (6 mL) under N2 atmosphere. The mixture was heated to 85° C. and stirred overnight. After that, the mixture was cooled to room temperature, poured into water (10 mL) and extracted with DCM (8 mL×2). The organic layers were washed with water (5 mL), brine (5 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with Petroleum ether/EtOAc=1:1) to give Compound 19-5 (110 mg, yield 39.1%). MS m/z: 424 [M+H]+.
  • Compound 19-5 (90 mg, 0.21 mmol), INT 3 (200 mg, 0.4 mmol), Cs2CO3 (190 mg, 0.6 mmol) and Cxiuma-Pd (15 mg, 0.02 mmol) were added successively into toluene/water=5:1 (2.4 mL). The reaction mixture was degassed with argon for 2 min. The mixture was heated to 105° C. under N2 atmosphere and stirred for 2 h in microwave. After that, the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL×2). The organic layer was washed with water (5 mL), brine (5 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10:1) to give Compound 19-6 (80 mg, yield 48.7%). MS m/z: 774 [M+H]+.
  • To a solution of Compound 19-6 (80 mg, 0.1 mmol) in DCM (2.0 mL) was added HCl (4 M in 1,4-dioxane, 2.0 mL) at room temperature. The reaction was stirred for 2 h and then concentrated to give Compound 19-7 (75 mg, crude). MS m/z: 730 [M+H]+.
  • To a solution of Compound 19-7 (75 mg crude, 0.1 mmol) in DMF (3 mL) was added CsF (308 mg, 2.0 mmol) at room temperature. The reaction mixture was heated to 40° C. and stirred for 4 h. Then the reaction mixture was filtered and the filtrate was purified by Prep-HPLC to give Compound 19 (23.3 mg, yield 39.3% for two steps).
  • 1H NMR (300 MHz, CD3OD): δ 9.41 (s, 1H), 8.46 (brs, 1H), 7.89-7.84 (m, 1H), 7.36-7.30 (m, 2H), 7.22 (d, J=2.4 Hz, 1H), 5.55-5.31 (m, 1H), 4.53-4.47 (m, 2H), 3.79-3.65 (m, 3H), 3.62-3.56 (m, 3H), 3.45 (s, 1H), 3.32-3.25 (m, 1H), 2.60-2.47 (m, 2H), 2.39-2.15 (m, 3H), 2.05 (s, 1H), 1.77 (s, 3H), 1.16 (s, 4H). MS m/z: 574 [M+H]+.
    • Example 21 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl methylcarbamate 2,2,2-trifluoroacetic acid (“Compound 20 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01294
  • To a solution of Compound 3A (99 mg, 0.17 mmol) and DIEA (1 mL) in DCM (10 mL) was added methylcarbamic chloride (99 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous NH4Cl solution (20 mL) and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • The crude product was purified by Pre-HPLC with the following condition (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 50% B in 38 min at a flow rate of 60 mL/min, 230 nm) and the product fractions were lyophilized to give Compound 20 (TFA salt) (75.4 mg, 0.10 mmol, 58.8% yield). MS m/z: 635 [M+H]+.
    • Example 22 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl dimethylcarbamate-2,2,2-trifluoroacetic acid_(“Compound 21 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01295
  • To a solution of Compound 3A (109.2 mg, 0.19 mmol) and pyridine (2 mL) in acetonitrile (10 mL) was added dimethylcarbamic chloride (3 drops). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Pre-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 50% B in 40 min at a flow rate of 60 mL/min, 230 nm) and the product fractions were lyophilized to give Compound 21 (TFA salt) (88 mg, 0.12 mmol, 61.0% yield). MS m/z: 649 [M+H]+.
    • Example 23 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((2-methylcyclopropyl)amino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (“Compound 22”)
  • Figure US20240376128A1-20241114-C01296
  • A solution of 2-methylcyclopropanecarboxylic acid (295 mg, 2.9466 mmol), DPPA (784 mg, 3.2237 mmol) and TEA (349 mg, 3.4490 mmol) in tert-butanol (10 mL) was stirred for 8 hours at 80° C. under nitrogen atmosphere. The solution was concentrated under vacuum to give crude Compound 22-1 (702 mg, 4.0996 mmol, 139.1301% yield). MS m/z: 172 [M+H]+.
  • A solution of Compound 22-1 (0.702 g, 4.0996 mmol) and hydrogen chloride (4 M in 1,4-dixoane, 2 mL) in DCM (10 mL) was stirred at room temperature for 20 h. The solution was concentrated under vacuum to give Compound 22-2 (1397 mg, 12.9855 mmol, 316.7498% yield). MS m/z: 72 [M+H]+.
  • A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (311 mg, 1.2319 mmol), N,N-diisopropylethylamine (504 mg, 3.8996 mmol) and Compound 22-2 (837 mg, 7.7801 mmol) in DCM (10 mL) was stirred 4 h at room temperature. The solution was diluted with 10% citric acid solution (10 mL). The organic layer was washed with 10 mL aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give Compound 22-3 (290 mg, 1.0100 mmol, 81.9912%). MS m/z: 287 [M+H]+.
  • A solution of INT 2 (241.1964 mg, 1.5150 mmol), Compound 22-3 (0.29 g, 1.0100 mmol) and potassium fluoride (176.0383 mg, 3.0301 mmol) in DMSO (10 mL) was stirred at 100° C. for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (20 mL) and extracted with EA (20 mL). The organic layer was washed with 10 mL aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuum. Then the residue purified by TLC to give Compound 22-4 (213 mg, 519.6899 μmol, 51.4529% yield). MS m/z: 410 [M+H]+.
  • A solution of Compound 22-4 (213 mg, 519.6899 μmol), toluene (5 mL), INT 3 (384 mg, 749.2177 mol), cataCXium A Pd G3 (39 mg, 53.5516 μmol), cesium carbonate (519 mg, 1.5929 mmol) and water (1 mL) was stirred at 100° C. for 14 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with water (15 mL) and extracted with EA (15 mL). The organic layer was washed with aqueous NaCl solution (10 mL) then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 22-5 (313 mg, 411.8570 μmol, 79.2506% yield). MS m/z: 760 [M+H]+.
  • A solution of Compound 22-5 (313 mg, 411.8570 μmol) and HCl (4 M in 1,4-dioxane, 1 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The solution was diluted with 10% NaHCO3 solution (10 mL) and extracted with DCM (10 mL). The organic layer was washed with aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 22-6 (236 mg, 329.6457 μmol, 80.0389% yield). MS m/z: 716 [M+H]+.
  • A solution of Compound 22-6 (236 mg, 329.6457 μmol) and CsF (233 mg, 1.5339 mmol) in DMF (10 mL) was stirred at room temperature for 20 hours under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL). The organic layer was washed with saturated aqueous NaCl solution (10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 15% B in 2 min, 15% B to 21% B in 13 min at a flow rate of 60 mL/min, 270 nm). The eluent was adjusted to pH=8. The acetonitrile in the eluent was concentrated. The resulting aqueous layer was extracted with EA and then the organic layer was dried, concentrated and lyophilized to give Compound 22 (79 mg, 141.1772 μmol, 42.8269% yield). MS m/z: 560 [M+H]+.
    • Example 24 Di-tert-butyl (((5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl) phosphate (“Compound 23”) ((5-ethynyl-6-fluoro-4-(8-fluoro-4-((trans-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl dihydrogen phosphate 2,2,2-trifluoroacetic acid (“Compound 24 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01297
  • A solution of 2-[tert-butoxy(chloromethyl)phosphoryl]oxy-2-methyl-propane (0.62 g, 2.5548 mmol), Compound 3 (1.02 g, 1.7660 mmol) and potassium carbonate (0.75 g, 5.4267 mmol) in N,N-dimethylformamide (20 mL) was stirred at 60° C. for 18 h. The reaction mixture was concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.05% TFA in water, B: CH3CN, Gradient: 25% B to 80% B in 60 min at a flow rate of 200 mL/min, 254 nm). The eluent was adjusted to pH=8 with saturated NaHCO3. The acetonitrile in the eluent was concentrated. The resulting aqueous layer was extracted with EA (200 mL×2) and then the organic layer was dried, concentrated and lyophilized to give Compound 23 (514 mg, 642.6697 μmol 36.3909% yield). MS m/z: 800 [M+H]+.
  • A solution of Compound 23 (0.31 g, 387.6022 μmol) and trifluoroacetic acid (2 mL) in dichloromethane (10 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.05% TFA in water, B: CH3CN, Gradient: 20% B to 50% B in 60 min at a flow rate of 70 mL/min, 242 nm) and lyophilized to give Compound 24 (TFA salt) (228 mg, 284.4312 μmol, 73.3823% yield). MS m/z: 688 [M+H]+.
    • Example 25 5-ethynyl-6-fluoro-4-(8-fluoro-4-((1-(fluoromethyl)cyclopropyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (“Compound 25”)
  • Figure US20240376128A1-20241114-C01298
  • 1-(fluoromethyl)cyclopropanamine (98 mg, 780.4281 μmol) was added into a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (210 mg, 831.8140 μmol) and N,N-disopropylethylamine (327 mg, 2.5301 mmol) in DCM (10 mL) at 0° C. Then the solution was stirred at room temperature for 3 h. The solution was diluted with 10% citric acid solution (50 mL). The organic layer was washed with aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give Compound 25-1 (303 mg, 993.0828 μmol, 119.3876% yield). MS m/z: 305 [M+H]+.
  • A solution of Compound 25-1 (303 mg, 993.0828 μmol), INT 2 (237 mg, 1.4887 mmol) and KF (186 mg, 3.2016 mmol) in DMSO (10 mL) was stirred at 85° C. for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with water (10 mL) and extracted with EA (10 mL). The organic layer was washed with 10 mL aqueous NaCl solution then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 25-2 (340 mg, 794.6705 μmol, 80.0207% yield. MS m/z: 428 [M+H]+.
  • A solution of Compound 25-2 (340 mg, 794.6705 μmol), toluene (7.5 mL), INT 3 (619 mg, 1.2077 mmol), cataCXium A Pd G3 (77 mg, 105.7300 μmol), Potassium phosphate (760 mg, 2.3326 mmol) and water (1.5 mL) was stirred at 105° C. for 3 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (15 mL) and extracted with EA (15 mL). The organic layer was washed with 10 mL aqueous NaCl solution then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 25-3 (312 mg, 401.0473 μmol, 50.4671% yield). MS m/z: 778 [M+H]+.
  • A solution of Compound 25-3 (312 mg, 401.0473 μmol) and HCl (4 M in 1,4-dioxane, 1 mL) in DCM (10 mL) was stirred at room temperature for 1 h. The solution was diluted with 10% NaHCO3 solution (20 mL). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 25-4 (325 mg, 442.8332 μmol, 110.4192% yield). MS m/z: 734 [M+H]+.
  • A solution of Compound 25-4 (325 mg, 442.8332 μmol) and CsF (301 mg, 1.9815 mmol) in DMF (10 mL) was stirred for 20 hours at 40° C. under nitrogen atmosphere. The solution was diluted with water (10 mL) and extracted with EA (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 10% B to 44% B in 55 min at a flow rate of 60 mL/min, 234 nm). The pH of the eluent was adjusted to 8 and the acetonitrile in the eluent was concentrated. The aqueous layer was extracted with EA and the resulting organic layer was dried, concentrated and lyophilized to give Compound 25 (75 mg, 129.8542 μmol, 29.3235% yield). MS m/z: 578 [M+H]+.
    • Example 26 4-(4-(cyclopropyl(methyl-d3)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (“Compound 26”)
  • Figure US20240376128A1-20241114-C01299
  • A solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (2172 mg, 10.2834 mmol) in EtOH (12 mL) was added NaBD4 (160 mg, 3.8225 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. The solution was quenched with water (0.5 mL) and concentrated in vacuum. The residue was purified by normal phase chromatography (silica gel cartridge, hexane/EA=1:1) to give Compound 26-1 (1485 mg, 6.8992 mmol, 67.0906% yield). MS: m/z: 215 [M+H]+.
  • A solution of Compound 26-1 (1485 mg, 6.8992 mmol) in DCM (10 mL) was added DAST (1.62 g, 10.0503 mmol) at −78° C. The reaction mixture was stirred at room temperature for 4 h. The solution was quenched with MeOH (0.5 mL) at 0° C., diluted with water (10 mL) and extracted with DCM (10 mL×3). The organic layer was washed with aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by normal phase chromatography (silica gel cartridge, hexane/EA=1:1) to give Compound 26-2 (1103 mg, 5.4550 mmol, 79.0668% yield). MS: m/z: 217 [M+H]+.
  • A solution of Compound 26-2 (1103 mg, 5.4550 mmol) in THF (10 mL) was added LiAlD4 (414 mg, 8.2730 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 3 h. The solution was quenched with water (0.4 mL), 15% sodium hydroxide solution (0.4 mL) and water (1.2 mL), filtered and concentrated in vacuum.
  • The residue was purified by normal phase chromatography (silica gel cartridge, DCM/MeOH=10:1) to give Compound 26-3 (707 mg, 4.3049 mmol, 78.9168% yield). MS: m/z: 165 [M+H]+.
  • A solution of Compound 26-3 (212 mg, 730.6853 μmol), Compound 4-4 (175 mg, 1.0656 mmol) and KF (254 mg, 4.3720 mmol) in DMSO (10 mL) was stirred at 100° C. for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated NaHCO3 aqueous solution (50 mL) and extracted with EA (2×30 mL). The organic layer was washed with aqueous NaCl solution (50 mL×2) then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15:1) to give Compound 26-4 (158 mg, 378.0724 μmol, 51.7422% yield). MS: m/z: 418 [M+H]+.
  • A solution of Compound 26-4 (158 mg, 378.0724 μmol), toluene (10 mL), INT-3 (340 mg, 663.3693 μmol), cataCXium A Pd G3 (82 mg, 112.5956 μmol)), cesium carbonate (416 mg, 1.2768 mmol) and water (2 mL) was stirred at 100° C. for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (2×50 mL). The organic layer was washed with 50 ml aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15:1) to give Compound 26-5 (203 mg, 264.3153 μmol, 69.9113% yield). MS: m/z: 768 [M+H]+.
  • A solution of Compound 26-5 (203 mg, 264.3153 μmol) and HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10% NaHCO3 solution (50 mL) and extracted with DCM (2×30 mL). The organic layer was washed with saturated aqueous NaCl solution (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 26-6 (279 mg, 385.3752 μmol, 145.8013% yield). MS: m/z: 724 [M+H]+.
  • A solution of Compound 26-6 (279 mg, 385.3752 μmol) and CsF (1226 mg, 8.0709 mmol) in DMF (10 mL) was stirred for 16 hours at 35° C. under nitrogen atmosphere. The solution was diluted with saturated aqueous NaHCO3 solution (50 mL) and extracted with EA (2×30 mL). The organic layer was washed with saturated aqueous NaCl solution (50 mL×2), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 45% B in 40 min at a flow rate of 60 mL/min, 240 n). The eluent was adjusted to pH=8 with saturated NaHCO3. The acetonitrile in the eluent was concentrated. The resulting aqueous layer was extracted with EA (100 mL×2) and then the organic layer was dried, concentrated and lyophilized to give Compound 26 (68 mg, 119.7963 μmol, 31.0856% yield). MS: m/z: 568 [M+H]+.
    • Example 27 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl sulfamate 2,2,2-trifluoroacetic acid (“Compound 27 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01300
  • To a solution of chlorosulfonyl isocyanate (7.5 mL) in acetonitrile (12 mL) was added formic acid (3.3 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour, then diluted with acetonitrile (24 mL). The mixture was stirred at room temperature for 3.5 hours. Then 2 mL of the solution was treated in another flask and stirred at 0° C., then Compound 3A (50 mg, 0.086 mmol) in DMAc (2 mL) was added dropwise. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Pre-HPLC with the following condition (Ultimate XB—C18, 30 mm×150 mm, 5 um; A: 0.1% TFA in water, B: CH3CN, Gradient: 10% B to 36% B in 60 min at a flow rate of 40 mL/min, 242 nm) and the product fractions were lyophilized to give Compound 27 (TFA salt, 37.9 mg). MS: m/z: 657[M+H]+.
    • Example 28 ethyl2-((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy) acetate 2,2,2-trifluoroacetic acid (“Compound 28 (TFA salt”)
  • Figure US20240376128A1-20241114-C01301
  • A solution of Compound 3A (151 mg, 0.26 mmol), K2CO3 (169 mg, 1.22 mmol) and ethyl 2-bromoacetate (44 mg, 0.26 mmol) in DMF (5 mL) was stirred at 80° C. for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Pre-HPLC with the following condition (Daisogel C18, 50 mm×250 mm, 10 um; A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 59% B in 48 min at a flow rate of 60 mL/min, 265 nm) and freeze-dried to give Compound 28 (TFA salt, 44.1 mg, 21.69% yield). MS: m/z: 664[M+H]+.
    • Example 29 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl (2-acetamidoethyl)(methyl)carbamate 2,2,2-trifluoroacetic acid (“Compound 29 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01302
  • To a solution of Compound 3A (404 mg, 0.66 mmol) and DIEA (1 mL) in DCM (10 mL) was added 4-nitrophenyl carbonochloridate (137 mg, 0.79 mmol). The resulting mixture was stirred for 25 minutes at room temperature, then tert-butyl (2-(methylamino)ethyl)carbamate (137 mg, 0.79 mmol) was added and stirred for 2 hours at room temperature. The mixture was diluted with water (20 mL) and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 29-1 (598 mg, 116.85% yield). MS: m/z: 778[M+H]+.
  • To a solution of Compound 29-1 (598 mg, 0.77 mmol) in DCM (10 mL) was added TFA (3 mL). The resulting mixture was stirred for 2.5 hours at room temperature, then concentrated under reduced pressure to give Compound 29-2. MS: m/z: 678[M+H]+.
  • A solution of Compound 29-2 (260 mg, 0.38 mmol), acetic anhydride (1 mL) and DIEA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL) and sat. NH4Cl (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Pre-HPLC with the following condition (Daisogel C18, 50 mm×250 mm, 10 um; A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 50% B in 40 min at a flow rate of 60 mL/min, 245 nm) and freeze-dried to give Compound 29 (TFA salt, 162.2 mg, 25.30% yield). MS: m/z: 720[M+H]+.
    • Example 30 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl methyl(2-(2,2,2-trifluoroacetamido)ethyl)carbamate 2,2,2-trifluoroacetic acid (“Compound 30 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01303
  • A solution of Compound 29-2 (260 mg, 0.38 mmol), trifluoroacetic anhydride (1 mL) and DIEA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL) and sat·NH4Cl (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Pre-HPLC with the following condition (Daisogel C18, 50 mm×250 mm, 10 um; A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 55% B in 50 min at a flow rate of 60 mL/min, 235 nm and freeze-dried to give Compound 30 (TFA salt, 70.5 mg, 20.66% yield). MS: m/z: 774[M+H]+.
    • Example 31 1-(((2-((((5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)carbonyl)(methyl)amino)ethyl)carbamoyl)oxy)ethyl isobutyrate 2,2,2-trifluoroacetic acid (“Compound 31 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01304
  • To a solution of Compound 29-2 (102 mg, 0.15 mmol), DIEA (1 mL) in DCM (5 mL) was added 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl isobutyrate (39 mg, 0.13 mmol), then stirred at room temperature for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Pre-HPLC with the following condition (Agela Durashell C18, 30 mm×250 mm, 10 um; A: 0.1% TFA in water, B: CH3CN, Gradient: 15% B to 49% B in 37 min at a flow rate of 40 mL/min, 240 nm) and freeze-dried to give Compound 31 (TFA salt, 57.1 mg, 39.96% yield). MS: m/z: 836[M+H]+.
    • Example 32 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1S,2S)-2-fluorocyclopropyl)(methyl)amino)-2-((2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid (“Compound 32 (TFA salt)”)
  • Figure US20240376128A1-20241114-C01305
  • To a solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (1.04 g, 4.92 mmol) in EtOH (6 mL) was slowly added NaBH4 (72 mg, 1.90 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with sat. NH4Cl (2 mL) and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with DCM:MeOH=50:1 to 20:1, v/v) to give Compound 32-1 (851 mg, 81.05% yield). MS: m/z: 214 [M+H]+.
  • To a solution of Compound 32-1 (851 mg, 3.99 mmol) in DCM (10 mL) was added a solution of DAST (970 mg, 6.02 mmol) drop-wise at −70° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was quenched with MeOH (2 mL), then diluted with water (10 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (30 mL, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with Hex:EtOAc=10:1 to 1:1, v/v) to give Compound 32-2 (401 mg, 46.68% yield). MS: m/z: 216 [M+H]+.
  • To a solution of Compound 32-2 (383 mg, 1.78 mmol) in THF (8 mL) was slowly added BH3 (3.5 mL, 1M in THF) at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 8 hours. The reaction was quenched with MeOH (2 mL) and concentrated under reduced pressure. The residue was dissolved in MeOH (4 mL) and stirred at reflux temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluted with Hex:EtOAc=100:1 to 1:1, v/v) to give Compound 32-3 (264 mg, 1.31 mmol, 73.72% yield). MS: m/z: 202 [M+H]+.
  • To a solution of Compound 32-3 (245 mg, 1.22 mmol) in THF (5 mL) was slowly added LiAlD4 (62 mg, 1.24 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (0.1 mL), NaOH (15%, 0.1 mL) and water (0.1 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with DCM:MeOH=10:1 to 2:1, v/v) to give Compound 32-4 (174 mg, 88.65% yield). MS: m/z: 162 [M+H]+.
  • To a solution of Compound 3A-4 (185 mg, 0.606 mmol), Compound 32-4 (97 mg, 0.602 mmol) in THF (5 mL) was added t-BuONa (73 mg, 0.760 mmol) in portions at −10° C. under nitrogen atmosphere. The reaction mixture was stirred for 3 hours. The mixture was allowed to warm to room temperature and extracted with EtOAc (30 mL). The organic layer was washed with brine (2×30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH=15:1, v/v) to give Compound 32-5 (127 mg, 48.73% yield). MS: m/z: 430 [M+H]+.
  • To a solution of Compound 32-5 (127 mg, 0.295 mmol), INT3 (203 mg, 0.396 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added Cs2CO3 (275 mg, 0.844 mmol) and cataCxium A Pd G3 (25 mg, 0.034 mmol). The reaction mixture was stirred at 100° C. for overnight under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH=15:1, v/v) to give Compound 32-6 (173 mg, 0.222 mmol, 75.07% yield). MS: m/z: 780 [M+H]+.
  • A solution of Compound 32-6 (173 mg, 0.222 mmol) and HCl (0.8 mL, 4M in dioxane) in acetonitrile (3 mL) was stirred at room temperature for 2 hours. The solution was diluted with sat. aq. NaHCO3 (20 mL), extracted with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Compound 32-7 (crude, 164 mg, 100.47% yield). MS: m/z: 736 [M+H]+.
  • To a solution of Compound 32-7 (164 mg, 0.223 mmol) in DMF (3 mL) was added CsF (0.35 g, 2.30 mmol). The reaction was stirred at 44° C. for 2 hours under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Daisogel C18, 50 mm×250 mm, 10 urn; A: 0.10% TFA in water, B: CH3CN, Gradient: 15% B to 48% B in 45 min at a flow rate of 60 mL/min, 235 nm) to freeze-dried to afford Compound 32 (TFA salt, 97.0 mg, 0.140 mmol, 62.75% yield). MS: m/z: 580 [M+H]+.
  • The following compounds in the Table 16 were synthesized using the above procedures or modification procedures:
  • TABLE 16
    Example Compound Structure IUNPAC Name
    33 Compound 33 (TFA salt)
    Figure US20240376128A1-20241114-C01306
         		4-(5-chloro-4-(cyclopropyl(methyl)amino)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyridin [4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro- naphthalen-2-ol 2,2,2-trifluoroacetic acid
    34 Compound 34
    Figure US20240376128A1-20241114-C01307
         		4-(4-(cyclopropylamino)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    35 Compound 35
    Figure US20240376128A1-20241114-C01308
         		4-(cyclopropyl(methyl)amino)-7-(8-ethynyl- 7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d] pyrimidine-5-carbonitrile
    36 Compound 36 (TFA salt)
    Figure US20240376128A1-20241114-C01309
         		4-(4-(cyclopropyl(2-methoxyethyl)amino)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro naphthalen-2-ol 2,2,2-trifluoroacetic acid
    37 Compound 37 (TFA salt)
    Figure US20240376128A1-20241114-C01310
         		4-(4-(cyclopropyl(2-fluoroethyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro- naphthalen-2-ol 2,2,2-trifluoroacetic acid
    38 Compound 38 (TFA salt)
    Figure US20240376128A1-20241114-C01311
         		Ethyl N-cyclopropyl-N-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)glycinate 2,2,2-trifluoroacetic acid
    39 Compound 39 (TFA salt)
    Figure US20240376128A1-20241114-C01312
         		N-cyclopropyl-N-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)acetamide 2,2,2-trifluoroacetic acid
    40 Compound 40 (TFA salt)
    Figure US20240376128A1-20241114-C01313
         		2-(cyclopropyl(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) amino)acetonitrile 2,2,2-trifluoroacetic acid
    41 Compound 41
    Figure US20240376128A1-20241114-C01314
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((trans-2-methoxycyclo- propyl)(methyl)amino)pyrido[4,3-d] pyrimidin-7-yl)naphthalen-2-ol
    42 Compound 42 (TFA salt)
    Figure US20240376128A1-20241114-C01315
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((trans-2-(methoxymethyl) cyclopropyl)(methyl)amino)pyrido[4,3-d] pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid
    43 Compound 43 (TFA salt)
    Figure US20240376128A1-20241114-C01316
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(methyl(trans-2-(trifluoro- methyl)cyclopropyl)amino)pyrido[4,3-d] pyrimidin-7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid
    44 Compound 44 (TFA salt)
    Figure US20240376128A1-20241114-C01317
         		trans-2-((7-(8-ethynyl-7-fluoro-3-hydroxy naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) (methyl)amino)cyclopropane-1-carbonitrile 2,2,2-trifluoroacetic acid
    Figure US20240376128A1-20241114-C01318
    45 Compound 45
    Figure US20240376128A1-20241114-C01319
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((2-methoxycyclopropyl) (methyl)amino)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol 2,2,2-trifluoroacetic acid
    46 Compound 46
    Figure US20240376128A1-20241114-C01320
         		4-(4-((2-(benzyloxy)cyclopropyl)(methyl) amino)-8-fluoro-2-(((2R,7aS)-2-fluoro- tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol
    47 Compound 47
    Figure US20240376128A1-20241114-C01321
         		4-(4-(cyclopropyl(ethyl)amino)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
    48 Compound 48
    Figure US20240376128A1-20241114-C01322
         		4-(4-(dicyclopropylamino)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol
    49 Compound 49
    Figure US20240376128A1-20241114-C01323
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(methyl(2-methylcyclo- propyl)amino)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol
    50 Compound 50
    Figure US20240376128A1-20241114-C01324
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(((1S,2S)-2-hydroxy- cyclopropyl)(methyl)amino)pyrido[4,3-d] pyrimidin-7-yl)naphthalen-2-ol
    51 Compound 51
    Figure US20240376128A1-20241114-C01325
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(methyl(spiro[2.2]pentan-1- yl)amino)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol
    52 Compound 52
    Figure US20240376128A1-20241114-C01326
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(methyl(spiro[2.3]hexan- 1-yl)amino)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol
    53 Compound 53
    Figure US20240376128A1-20241114-C01327
         		4-(4-((3-oxabicyclo[3.1.0]hexan-6-yl)amino)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol
    54 Compound 54
    Figure US20240376128A1-20241114-C01328
         		4-(4-((3-oxabicyclo[3.1.0]hexan-6-yl)(methyl) amino)-8-fluoro-2-(((2R,7aS)-2-fluoro tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol
    55 Compound 55
    Figure US20240376128A1-20241114-C01329
         		4-(4-(bicyclo[4.1.0]heptan-7-ylamino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d] pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen- 2-ol
    56 Compound 56
    Figure US20240376128A1-20241114-C01330
         		4-(4-(bicyclo[4.1.0]heptan-7-yl(methyl) amino)-8-fluoro-2-(((2R,7aS)-2-fluoro- tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol
    57 Compound 57
    Figure US20240376128A1-20241114-C01331
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((1-(trifluoromethyl) cyclopropyl)amino)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol
    58 Compound 58
    Figure US20240376128A1-20241114-C01332
         		5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((1-(methoxymethyl) cyclopropyl)amino)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol
    59 Compound 59
    Figure US20240376128A1-20241114-C01333
         		1-((7-(8-ethynyl-7-fluoro-3-hydroxy- naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)(methyl) amino)cyclopropane-1-carbonitrile
    • Pharmacological Experiments 1. SOS1 Catalyzed Nucleotide Exchange Assay
  • The inhibition activity of each of compounds on GDP form K-Ras was evaluated by SOS1 catalyzed nucleotide exchange assays. K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WI proteins were used in this assay.
  • Briefly, K-Ras (His tag, aa 1-169) pre-loaded with GDP was pre-incubated with each of compounds in the presence of 10 nM GDP in a 384-well plate (Greiner) for 15-60 mins, then purified SOS1 Ext (Flag tag, aa 564-1049), BODIPY™ FL GTP (Invitrogen) and monoclonal antibody anti 6HIS—Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 4 hours at 25° C. (Specially, we did not add SOS1 in the K-Ras G13D assay). Wells containing the same percent of DMSO served as vehicle control, and wells without K-Ras served as low control. TR-FRET signals were read on Tecan Spark multimode microplate reader. The parameters were F486: Excitation 340 nm, Emission 486 nm, Lag time 100 pas, Integration time 200 pas; F515: Excitation 340 nm, Emission 515 nm, Lag time 100 pas, Integration time 200 pas. TR-FRET ratios for each individual wells were calculated by equation: TR-FRET ratio=(Signal F515/Signal F486)*10000. The percent of activation of compounds treated wells were normalized between vehicle control and low control (00 Activation=(TR-FRET ratioCompound treated−TR-FRET ratioLow control)/(TR-FRET ratioVehicle control−TR-FRET ratioLow control)*1000%). Then the data were analyzed either by filling a 4-parameter logistic model or by Excel to calculate IC50 values. The results are shown in the following Table 17.
  • 2. GTP-K-Ras and cRAF Interaction Assay
  • The inhibition activity of each of compounds on GTP form K-Ras was evaluated by GppNp-K-Ras and cRAF interaction assays. GppNp is an analog of GTP. K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WI proteins were used in this assay.
  • Briefly, K-Ras (His tag, aa 1-169) pre-loaded with GppNp was pre-incubated with each of compounds in the presence of 200 μM GTP in a 384-well plate (Greiner) for 15-60 mins, then cRAF RBD (GST tag, aa 50-132, CreativeBioMart), monoclonal antibody anti GST-d2 (Cisbio) and monoclonal antibody anti 6HIS—Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 2 hours at 25° C. Wells containing same percent of DMSU served as vehicle control, and wells without K-Ras served as low control. HTRP signals were read on Tecan Spark multimode microplate reader and HTRF ratios were calculated under manufacturer's instructions.
  • The percent of activation of compounds treated wells were normalized between vehicle control and low control (% Activation=(HTRF ratioCompound treated−HTRF ratioLow control)/(HTRF ratioVehicle control−HTRF ratioLow control)*100%). Then the data were analyzed either by fitting a 4-parameter logistic model or by Excel to calculate IC50 values. The results are shown in the following Table 17.
  • TABLE 17
    Biochemical assays, IC50 (nM)
    Com- K-Ras G12D K-Ras G12V K-Ras G12C K-Ras G13D
    pound GDP GppNp GDP GppNp GDP GppNp GDP GppNp
    Com- 3.90 50.2 0.683 204 4.21 426 15.2 10.1
    pound 1
    Com- 4.07 122 2.17 232
    pound 2
    Com- 2.64 28.3 2.77 77.9 3.21 283 4.98 6.97
    pound 3
    Com- 1.21 22.2 1.97 54.8 0.526 122 0.939 2.77
    pound 3A
    Com- 13.3 206 12.2 770
    pound 3B
    Com 3.41 88.8 0.949 234 3.83 587 10.1 13.7
    pound 4
    Com- 2.84 65.2 3.23 145 2.48 317 3.29 6.29
    pound 5
    Com- 1.32 118 4.43 167 3.03 564 4.38 8.55
    pound 6
    Com- 0.701 17.6 1.46 46.6
    pound 7
    Com- 46.9 801 >1000
    pound 8
    Com- 2.00 66.7 4.42 161
    pound 9
    Com- 24.20 519 5.98 736
    pound 10
    Com- 12.5 252 8.13 307
    pound 11
    Com- 32.9 460 7.39 1127
    pound 12
    Com- 30.3 1308 5.11 1823
    pound 13
    Com- 18.0 607.00 8.85 >1000
    pound 14
    Com- 3.16 172 6.53 568 3.88 >1000
    pound 15
    Com- 1.98 90.5 3.81 441 5.21 731 6.97 10.4
    pound 16
    Com- 8.94 574 8.24 984
    pound 17
    Com- 16.3 637 2.27 1587 13.9 48.3
    pound 18
    Com- 27.3 1477 9.60 3653 >100 >100
    pound 19
    Com- 12.8 730 2.96 1302
    pound 22
    Com- 8.59 320 2.97 >1000
    pound 25
    Com- 6.92 126 1.89 172 10.4 20.3
    pound 26
    Com- 6.07 657 6.17 >1000
    pound 33
    Com- 76.2 704 24.0 >1000
    pound 34
    Com- 380 >1000 117 >1000
    pound 35
    Com- 61.7 >1000 18.4 >1000
    pound 36
    Com- 77.7 >1000 24.5 >1000
    pound 37
    Com- 222 >1000 121 >1000
    pound 38
    Com- 282 >1000 25.9 >1000
    pound 41
    Com- 1944 >1000 34.7 >1000
    pound 42
    Com- 75.9 >1000 20.2 >1000
    pound 43
    Com- 16.3 >1000 13.9 >1000
    pound 44
    Com- 1.72 156 1.13 292 4.69 872 5.07 13.1
    pound 47
    Com- 134 2616 10.2 3706 50.0 >100
    pound 48
    Com- 1.99 222 1.11 333 6.01 ~1000 9.24 20.4
    pound 49
    Com- 61.7 744 16.2 >1000
    pound 51
    Com- 208 >1000 76.0 >1000
    pound 52
    Com- 17.1 678 5.39 1364
    pound 53
    Com- 774.1 1531 16.3 3719
    pound 55
    Com- 157 >1000 15.1 >1000
    pound 57
    Com- 25.9 >1000 3.55 >1000
    pound 58
    Com- 62.4 3193 36.7 4466 200 >100
    pound 59
    Biochemical assays, IC50 (nM)
    Com- K-Ras WT K-Ras G12A K-Ras G12R K-Ras Q61H
    pound GDP GppNp GDP GppNp GDP GppNp GDP GppNp
    Com- 3.23 108 5.60 421 2.93 86.4 3.93 144
    pound 1
    Com- 8.69
    pound 2
    Com- 2.40 112 3.83 272 3.25 30.3 2.42 45.3
    pound 3
    Com- 0.707 77.9 0.999 149 1.04 42.9 0.729 70.0
    pound 3A
    Com-
    pound 3B
    Com 8.89 179 6.97 308 5.37 97.7 4.46 117
    pound 4
    Com- 3.41 144 7.27 645 3.39 90.3 1.62 137
    pound 5
    Com- 4.24 218 6.09 >1000 3.11 101 2.87 388
    pound 6
    Com-
    pound 7
    Com-
    pound 8
    Com-
    pound 9
    Com- 29.2
    pound 10
    Com- 19.0
    pound 11
    Com- 43.4
    pound 12
    Com- 32.3 1628
    pound 13
    Com-
    pound 14
    Com-
    pound 15
    Com- 7.40 400 10.7 >1000 5.74 501 4.51 436
    pound 16
    Com-
    pound 17
    Com- 6.59 2143
    pound 18
    Com- 55.0 2870
    pound 19
    Com- 8.39
    pound 22
    Com-
    pound 25
    Com- 10.1 369 13.5 411 8.85 154 8.56 172
    pound 26
    Com-
    pound 33
    Com-
    pound 34
    Com-
    pound 35
    Com-
    pound 36
    Com-
    pound 37
    Com-
    pound 38
    Com-
    pound 41
    Com-
    pound 42
    Com-
    pound 43
    Com-
    pound 44
    Com- 5.12 329 10.4 >1000 2.56 160 2.84 575
    pound 47
    Com- 140
    pound 48
    Com- 8.60 315 25.2 >1000 7.79 144 4.85 230
    pound 49
    Com-
    pound 51
    Com-
    pound 52
    Com- 8.33
    pound 53
    Com- 29.40
    pound 55
    Com-
    pound 57
    Com-
    pound 58
    Com- 214
    pound 59
    • 3. Phospho-ERK1/2(THR202/TYR204) HTRF Assay
  • p-ERK (MAPK pathway) inhibition activity of each of compounds in a variety of K-Ras mutant and K-Ras WT cell lines indicated in Table 18 was evaluated. MKN-1 with K-Ras WT amplification is also a K-Ras dependent cell line.
  • TABLE 18
    Cell
    seeding
    density,
    K-Ras cells/ Culture Assay Cell
    Cell lines mutation well medium medium incubator
    AGS G12D 60000 F-12K, F-12K, 37° C.,
    10% FBS 0.1% FBS 5% CO2
    SW620 G12V 60000 L-15, L-15, 37° C.,
    10% FBS 0.1% FBS 100% Air
    NCI-H358 G12C 40000 RPMI 1640, RPMI 1640, 37° C.,
    10% FBS 0.1% FBS 5% CO2
    NCI-H747 G13D 40000 RPMI 1640, RPMI 1640, 37° C.,
    10% FBS 0.1% FBS 5% CO2
    RERF-LC-Ad1 G12A 30000 RPMI 1640, RPMI 1640, 37° C.,
    10% FBS 0.1% FBS 5% CO2
    TCC-PAN2 G12R 20000 RPMI 1640, RPMI 1640, 37° C.,
    10% FBS 0.1% FBS 5% CO2
    NCI-H460 Q61H 30000 RPMI 1640, PMI 1640, 37° C.,
    10% FBS 0.1% FBS 5% CO2
    MKN-1 WT 30000 RPMI 1640, RPMI 1640, 37° C.,
    10% FBS 0.1% FBS 5% CO2
  • Each of cells in culture medium was seeded in 96-well plates at density indicated in Table 18 and then put in a cell incubator to incubate overnight. The next day, the culture medium was removed and the compound diluted in assay medium was added in each well. After 2 hours incubation in a cell incubator, the assay medium in 96-well plates was removed, then 50 L of 1× blocking reagent-supplemented lysis buffer (Cisbio) was added and the plates were incubated at 25° C. for 45 min with shaking. 10 μL of cell lysates from the 96-well plates were transferred to a 384-well plate (Greiner) containing 2.5 L/well HTRF® pre-mixed antibodies (Cisbio 64AERPEH). The plate was incubated 4 hours at 25° C. and then read HTRF signals on Tecan Spark multimode microplate reader. The data were analyzed using a 4-parameter logistic model to calculate IC50 values. The results are shown in the following Table 19:
  • TABLE 19
    p-ERK, IC50(nM)
    Compound AGS SW620 NCI-H358 NCI-H747 RERF-LC-Ad1 TCC-PAN2 NCI-H460 MKN-1
    Compound 1 23.8 9.18 8.93 6.50 8.32 760 63.6 10.6
    Compound 2 27.8 17.4
    Compound 3 4.74 2.69
    Compound 3A 4.09 0.969 3.49 3.41 4.05 201 10.3 1.93
    Compound 4 27.0 10.0 11.5 7.28 392 38.3 14.4
    Compound 5 13.8 7.37 17.4 26.2 20.0 780 113 27.4
    Compound 6 4.81 5.96 75.1 7.90 3.70 278 51.2 3.82
    Compound 7 7.23 6.36
    Compound 10 64.7
    Compound 11 23.0
    Compound 12 64.4
    Compound 13 34.8
    Compound 15 23.5 2.75
    Compound 16 28.1 2.28 60.1 20.1 ~1000 82.7 13.8
    Compound 17 182 54.8
    Compound 18 49.3
    Compound 19 89.2
    Compound 22 28.6
    Compound 25 305 52.1
    Compound 26 36.2 8.74 18.8
    Compound 33 38.6 8.39
    Compound 47 14.8 8.90 121 16.8 455 45.6 18.6
    Compound 49 56.9 44.1 68.9 32.3 925 71.0 25.9
    Compound 53 165
    Compound 58 65.3
    • 4. Cell Growth Inhibition Assay
  • The cell growth inhibition activity of each of compounds was tested by performing cell growth inhibition assays on a variety of K-Ras mutant and K-Ras WT cell lines indicated in Table 20.
  • TABLE 20
    Cell
    seeding
    K-Ras density, Culture Assay Cell
    Cell lines mutation cells/well medium format incubator
    AGS G12D  500 F-12K, 2D 37° C.,
    10% FBS 5% CO2
    AsPC-1 G12D 1000 RPMI 1640, 2D 37° C.,
    10% FBS 5% CO2
    SW620 G12V 1500 L-15, 2D 37° C.,
    10% FBS 100% Air
    Capan-2 G12V 1500 McCoy′5A, 3D 37° C.,
    10% FBS 5% CO2
    NCI-H358 G12C 1500 RPMI 1640, 3D 37° C.,
    10% FBS 5% CO2
    NCI-H747 G13D 1500 RPMI 1640, 3D 37° C.,
    10% FBS 5% CO2
    RERF-LC-Ad1 G12A 3000 RPMI 1640, 3D 37° C.,
    10% FBS 5% CO2
    TCC-PAN2 G12R  500 RPMI 1640, 3D 37° C.,
    10% FBS 5% CO2
    NCI-H460 Q61H  300 RPMI 1640, 3D 37° C.,
    10% FBS 5% CO2
    MKN-1 WT 1500 RPMI 1640, 3D 37° C.,
    10% FBS 5% CO2
    • 2D Cell Growth Inhibition Assays
  • Each of cells in culture medium was plated in TC-treated 96-well plates at a density indicated in Table 20 and incubated in a cell incubator overnight. The next day, each of compounds was diluted in culture medium and added to the plates. After 6 days incubation in cell incubator, the cell viability was detected by CellTiter-Glo® Cell Viability Assay kit (Promega). Luminescent signals were read on Tecan Spark multimode microplate reader and analyzed using a 4-parameter logistic model to calculate absolute IC50 values. The results are shown in the following Table 21.
    • 3D Cell Growth Inhibition Assays
  • Each of cells in culture medium was plated in ultra-low attachment-coated 96-well plates at a density indicated in Table 20 and incubated in a cell incubator overnight. The next day, each of compounds was diluted in culture medium and added to the plates. After 6 days incubation in cell incubator, the cell viability was detected by CellTiter-Glo® 3D Cell Viability Assay kit (Promega). Luminescent signals were read on Tecan Spark multimode microplate reader and analyzed using a 4-parameter logistic model to calculate absolute IC50 values. The results are shown in the following Table 21.
  • TABLE 21
    Cell Growth Inhibition, IC50(nM)
    Compound AGS AsPC-1 SW620 Capan-2 NCI-H358 NCI-H747 RERF-LC-Ad1 TCC-PAN2 NCI-H460 MKN-1
    Compound 1 38.8 751 19.5 112 227 48.5 392 >1000 ~1000 61.0
    Compound 2 50.9 949 62.5
    Compound 3 12.0 78.4 4.32
    Compound 3A 4.99 61.3 2.28 10.4 46.6 17.6 83.6 602 141 15.4
    Compound 3B 87.8 1288 120
    Compound 4 41.4 772 22.7 72.1 59.6 802 508 95.3
    Compound 5 34.7 467 14.1 124 165 89.1 >1000 >1000 77.4
    Compound 6 17.7 53.5 21.2 121 14.5 22.9 284 >1000 382 52.3
    Compound 7 4.69 41.9 2.98
    Compound 10 123
    Compound 11 50.5
    Compound 12 406 2932 144
    Compound 13 99.9
    Compound 14 259
    Compound 15 24.1 122 12.9
    Compound 16 22.0 142 14.4 51.6 187 41.2 >1000 402 75.3
    Compound 17 94.2 555 110
    Compound 18 135
    Compound 22 41.6
    Compound 25 243 2175 97.7
    Compound 26 118 776 20.5 99.2
    Compound 33 97.9 703 71.0
    Compound 47 38.1 476 42.8 231 239 57.4 >1000 727 70.0
    Compound 49 105 1056 15.1 76.4 211 79.7 >1000 646 137
    Compound 53 37.2
    Compound 58 158
    • 5. Mouse Pharmacokinetic Study
  • The purpose of this study was to evaluate the pharmacokinetic properties of compounds in Balb/c mouse (♀) following single dose administration. Six mice were needed for each compound and the six mice were divided into two groups (n=3/group), group A and group B. Mice in group A were treated with a single 3 mg/kg dose of compound (iv). Mice in group B were treated with a single 10 mg/kg dose of compound (po). For each mouse in group A, blood samples were collected at the time point of 0.083, 0.5, 1, 2, 4 and 8 h post-dose. For each mouse in group B, blood samples were collected at the time point of 0.5, 1, 2, 4, 6 and 8 h post-dose. Blood samples were placed on ice until centrifugation to obtain plasma samples. The plasma samples were stored at −80° C. until analysis. The concentration of compound in plasma samples was determined using a LC-MS/MS method. The results are shown in the following Table 22.
  • For the prodrug, only the oral PK study was performed and the dosage was adjusted to be equal to 10 mg/kg of parent drug. The concentrations of both prodrug and parent drug in plasma were determined using a LC-MS/MS method. The results are shown in the following Table 23.
  • TABLE 22
    10 mg/kg, po
    Cmax AUC0-8h
    Compound (ng/ml) (ng · h/mL)
    Compound 1 1118 3001
    Compound 2 73.6 151
    Compound 3 947 3148
    Compound 3A 490 1258
    Compound 4 1953 5635
    Compound 5 91.3 168
    Compound 6 896 3454
    Compound 7 433 1376
    Compound 15 190 592
    Compound 16 165 696
    Compound 26 813 2588
  • TABLE 23
    Equal to 10 mg/kg of parent drug, po
    Cmax AUC0-8h
    Compound Analyte (ng/mL) (ng · h/mL)
    Compound 8 Compound 8 4963 18296
    Compound 4 1091 4013
    Compound 20 Compound 20 3483 11939
    Compound 3A 541 1463

Claims (21)

What is claimed is:
1-58. (canceled)
59. A compound of Formula (IB), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:
Figure US20240376128A1-20241114-C01334
Wherein,
R2a is selected from hydrogen, deuterium, —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, —N(Rb)2, —ORb, —SRb, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, —C2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —N(Rc)2, —ORc, —SRc, —S(═O)Rd, —S(═O)2Rd, —C(═O)Rd, —C(═O)ORc, —OC(═O)Rd, —C(═O)N(Rc)2, —NRcC(═O)Rd, —OC(═O)ORc, —NRcC(═O)ORd, —OC(═O)N(Rc)2, —NRcC(═O)N(Rc)2, —S(═O)ORc, —OS(═O)Rd, —S(═O)N(Rc)2, —NRcS(═O)Rd, —S(═O)2ORc, —OS(═O)2Rd, —S(═O)2N(Rc)2, —NRcS(═O)2Rd, —OS(═O)2ORc, —NRcS(═O)2ORc, —OS(═O)2NRc, —NRcS(═O)2N(Rc)2, —P(Rc)2, —P(═O)(Rd)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
RS1 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R61)2, —OR61, —SR61, —S(═O)R62, —S(═O)2R62, —C(═O)R62, —C(═O)OR61, —OC(═O)R62, —C(═O)N(R61)2, —NR61C(═O)R62, —OC(═O)OR61, —NR61C(═O)OR61, —NR61C(═S)OR61, —OC(═O)N(R61)2, —NR61C(═O)N(R61)2, —S(═O)OR61, —OS(═O)R62, —S(═O)N(R61)2, —NR61S(═O)R62, —S(═O)2OR61, —OS(═O)2R62, —S(═O)2N(R61)2, —NR61S(═O)2R62, —OS(═O)2OR61, —NR61S(═O)2OR61, —OS(═O)2N(R61)2, —NR61S(═O)2N(R61)2, —P(R61)2, —P(═O)(R62)2,
Figure US20240376128A1-20241114-C01335
3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R63)2, —OR63, —SR63, —S(═O)R64, —S(═O)2R64, —C(═O)R64, —C(═O)OR64, —OC(═O)R64, —C(═O)N(R63)2, —NR63C(═O)R64, —OC(═O)OR63, —NR63C(═O)OR63, —NR63C(═S)OR63, —OC(═O)N(R63)2, —NR63C(═O)N(R63)2, —S(═O)OR63, —OS(═O)R64, —S(═O)N(R63)2, —NR63S(═O)R64, —S(═O)2OR63, —OS(═O)2R64, —S(═O)2N(R63)2, —NR63S(═O)2R64, —OS(═O)2OR63, —NR63S(═O)2OR63, —OS(═O)2N(R63)2, —NR63S(═O)2N(R63)2, —P(R63)2, —P(═O)(R64)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, two RS1 together with the carbon atom to which they are both attached form
Figure US20240376128A1-20241114-C01336
a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said
Figure US20240376128A1-20241114-C01337
3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more R16c;
Optionally, two adjacent RS1 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R16a;
Optionally, two nonadjacent RS1 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S═O or S(═O)2; the hydrogen on the each of carbon atoms or N atoms is optionally independently substituted with Ri6e;
Y is a bond, O, S, S(═O), S(═O)2 or NR6a;
R2 is selected from -L5-(3-12 membered heterocyclyl), -L5-(3-12 membered cycloalkyl), -L5-(6-12 member aryl), -L5-(5-12 membered heteroaryl), -L5—N(R7a)2, or
Figure US20240376128A1-20241114-C01338
Each of L5 at each occurrence is independently selected from a bond or C1-10 alkylene optionally substituted with one or more R16n;
Said 3-12 membered heterocyclyl in -L5-(3-12 membered heterocyclyl) is optionally substituted with one or more R16o;
Said 3-12 membered cycloalkyl in -L5-(3-12 membered cycloalkyl) is optionally substituted with one or more R16o;
Said 6-12 member aryl in -L5-(6-12 member aryl) is optionally substituted with one or more R16o;
Said 5-12 membered heteroaryl in -L5-(5-12 membered heteroaryl) is optionally substituted with one or more R16o;
L6 is selected from a bond or C1-10 alkylene optionally substituted with one or more R16p;
L7 is selected from a bond or C1-10 alkylene optionally substituted with one or more R16q;
L8 is selected from a bond or C1-10 alkylene optionally substituted with one or more R16r;
Ring C or ring D is a 3-10 membered heterocyclic ring which is optionally further contains 1, 2, or 3 heteroatoms selected from N, O or S;
Ring E is selected from a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein the moiety of -L7- and -L8-X6 are attached to the same atom or different atoms of the ring E;
X6 is selected from —N(R65)2, —OR65, —SR65, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally independently substituted with one or more R16s;
Each of RS5 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6-alkenyl, haloC2-alkenyl, —C2-alkynyl, haloC2-alkynyl, —CN, —NO2, —N3, oxo, —N(R66)2, —OR66, —SR66, —S(═O)R67, —S(═O)2R67, —C(═O)R67, —C(═O)OR66, —OC(═O)R67, —C(═O)N(R66)2, —NR66C(═O)R67, —OC(═O)OR66, —NR66C(═O)OR66, —NR66C(═S)OR66, —OC(═O)N(R66)2, —NR66C(═O)N(R66)2, —S(═O)OR66, —OS(═O)R67, —S(═O)N(R66)2, —NR66S(═O)R67, —S(═O)2OR66, —OS(═O)2R67, —S(═O)2N(R66)2, —NR66S(═O)2R67, —OS(═O)2OR66, —NR66S(═O)2OR66, —OS(═O)2N(R66)2, —NR66S(═O)2N(R66)2, —P(R66)2, —P(═O)(R67)2,
Figure US20240376128A1-20241114-C01339
3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-alkynyl, —CN, —NO2, —N3, oxo, —N(R68)2, —OR68, —SR68, —S(═O)R69, —S(═O)2R69, —C(═O)R69, —C(═O)OR68, —OC(═O)R69, —C(═O)N(R68)2, —NR68C(═O)R69, —OC(═O)OR68, —NR68C(═O)OR68, —NR68C(═S)OR68, —OC(═O)N(R68)2, —NR68C(═O)N(R68)2, —S(═O)OR68, —OS(═O)R69, —S(═O)N(R68)2, —NR68S(═O)R69, —S(═O)2OR68, —OS(═O)2R69, —S(═O)2N(R68)2, —NR68S(═O)2R69, —OS(═O)2OR68, —NR68S(═O)2OR68, —OS(═O)2N(R68)2, —NR68S(═O)2N(R68)2, —P(R68)2, —P(═O)(R69)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, two RS5 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 membered carbocylic ring or
Figure US20240376128A1-20241114-C01340
3-10 heterocyclic ring is optionally substituted with one or more R16t;
Optionally, two adjacent RS5 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R16u;
Optionally, two nonadjacent RS5 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S═O or S(═O)2; the hydrogen on the each of carbon atoms or N atoms is optionally independently substituted with R16v;
q5 is selected from 0, 1, 2, 3, 4, 5 or 6;
Each of RS6 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R71)2, —OR71, —SR71, —S(═O)R72, —S(═O)2R71, —C(═O)R72, —C(═O)OR71, —OC(═O)R72, —C(═O)N(R71)2, —NR71C(═O)R72, —OC(═O)OR71, —NR71C(═O)OR71, —OC(═O)N(R71)2, —NR71C(═O)N(R71)2, —S(═O)OR71, —OS(═O)R72, —S(═O)N(R71)2, —NR71S(═O)R72, —S(═O)2OR71, —OS(═O)2R72, —S(═O)2N(R71)2, —NR71S(═O)2R72, —OS(═O)2OR71, —NR71S(═O)2OR72, —OS(═O)2N(R71)2, —NR71S(═O)2N(R71)2, —P(R71)2, —P(═O)(R72)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6 alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R73)2, —OR73, —SR73, —S(═O)R74, —S(═O)2R73, —C(═O)R74, —C(═O)OR73, —OC(═O)R74, —C(═O)N(R73)2, —NR73C(═O)R74, —OC(═O)OR73, —NR73C(═O)OR73, —OC(═O)N(R73)2, —NR73C(═O)N(R73)2, —S(═O)OR73, —OS(═O)R74, —S(═O)N(R73)2, —NR73S(═O)R74, —S(═O)2OR73, —OS(═O)2R74, —S(═O)2N(R73)2, —NR73S(═O)2R74, —OS(═O)2OR73, —NR73S(═O)2OR74, —OS(═O)2N(R73)2, —NR73S(═O)2N(R73)2, —P(R73)2, —P(═O)(R74)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
q6 is selected from 0, 1, 2, 3, 4, 5 or 6;
R4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl,
Figure US20240376128A1-20241114-C01341
 wherein said 6-10 membered aryl, 5-10 membered heteroaryl,
Figure US20240376128A1-20241114-C01342
 is optionally independently substituted with one or more R41;
Z at each occurrence is independently selected from C or N;
Ring G at each occurrence is independently selected from a 6 membered aryl ring or a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring when Z is selected from C;
Ring G at each occurrence is selected from a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered heterocyclic ring when Z is selected from N;
R41 at each occurrence is independently selected from deuterium, halogen, —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, —CN, —NO2, —N3, oxo, —N(R75)2, —OR75, —SR75, —S(═O)R76, —S(═O)2R76, —C(═O)R76, —C(═O)OR75, —OC(═O)R76, —C(═O)N(R75)2, —NR75C(═O)R76, —OC(═O)OR75, —NR75C(═O)OR75, —OC(═O)N(R75)2, —NR75C(═O)N(R75)2, —S(═O)OR75, —OS(═O)R76, —S(═O)N(R75)2, —NR75S(═O)R76, —S(═O)2OR75, —OS(═O)2R76, —S(═O)2N(R75)2, —NR75S(═O)2R76, —OS(═O)2OR75, —NR75S(═O)2OR75, —OS(═O)2N(R75)2, —NR75S(═O)2N(R75)2, —P(R75)2, —P(═O)(R75)2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R77)2, —OR77, —SR77, —S(═O)R78, —S(═O)2R78, —C(═O)R78, —C(═O)OR77, —OC(═O)R78, —C(═O)N(R77)2, —NR77C(═O)R78, —OC(═O)OR77, —NR77C(═O)OR77, —OC(═O)N(R77)2, —NR77C(═O)N(R77)2, —S(═O)OR77, —OS(═O)R78, —S(═O)N(R77)2, —NR77S(═O)R78, —S(═O)2OR77, —OS(═O)2R78, —S(═O)2N(R77)2, —NR77S(═O)2R78, —OS(═O)2OR77, —NR77S(═O)2OR77, —OS(═O)2N(R77)2, —NR77S(═O)2N(R77)2, —P(R77)2, —P(═O)(R78)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Each of (R51 and R52) is independently selected from hydrogen, deuterium, halogen, —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, —CN, —NO2, —N3, oxo, —N(R81)2, —OR81, —SR81, —S(═O)R82, —S(═O)2R82, —C(═O)R82, —C(═O)OR81, —OC(═O)R82, —C(═O)N(R81)2, —NR81C(═O)R82, —OC(═O)OR81, —NR81C(═O)OR81, —OC(═O)N(R81)2, —NR81C(═O)N(R81)2, —S(═O)OR81, —OS(═O)R82, —S(═O)N(R81)2, —NR81S(═O)R82, —S(═O)2OR81, —OS(═O)2R82, —S(═O)2N(R81)2, —NR81S(═O)2R82, —OS(═O)2OR81, —NR81S(═O)2OR81, —OS(═O)2N(R81)2, —NR81S(═O)2N(R81)2, —P(R81)2, —P(═O)(R82)2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, haloC2-6alkenyl, —C2-6alkynyl, haloC2-6alkynyl, —CN, —NO2, —N3, oxo, —N(R83)2, —OR83, —SR83, —S(═O)R84, —S(═O)2R84, —C(═O)R84, —C(═O)OR83, —OC(═O)R83, —C(═O)N(R83)2, —NR83C(═O)R84, —OC(═O)OR83, —NR83C(═O)OR83, —OC(═O)N(R83)2, —NR83C(═O)N(R84)2, —S(═O)OR83, —OS(═O)R84, —S(═O)N(R83)2, —NR83S(═O)R84, —S(═O)2OR83, —OS(═O)2R84, —S(═O)2N(R83)2, —NR83S(═O)2R84, —OS(═O)2OR83, —NR83S(═O)2OR83, —OS(═O)2N(R83)2, —NR83S(═O)2N(R83)2, —P(R83)2, —P(═O)(R84)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Each of (R6a, R7a, R61, R63, R65, R66, R68, R71, R73, R75, R77, R81 and R83) at each occurrence is independently selected from hydrogen, deuterium, halogen, —C1-10alkyl, haloC1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —S(═O)Ra, —S(═O)2Ra, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Ra)2, —S(═O)ORa, —S(═O)N(Ra)2, —S(═O)2ORa, —S(═O)2N(Ra)2, —P(═O)(Ra)2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-10alkyl, haloC1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6 alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —N(Rc)2, —ORc, —SR, —S(═O)Rd, —S(═O)2Rd, —C(═O)Rd, —C(═O)ORc, —OC(═O)Rd, —C(═O)N(Rc)2, —NRcC(═O)Rd, —OC(═O)ORc, —NRcC(═O)ORd, —OC(═O)N(Rc)2, —NRcC(═O)N(Rc)2, —S(═O)ORc, —OS(═O)Rd, —S(═O)N(Rc)2, —NRcS(═O)Rd, —S(═O)2ORc, —OS(═O)2Rd, —S(═O)2N(Rc)2, —NRcS(═O)2Rd, —OS(═O)2ORc, —NRcS(═O)2ORc, —OS(═O)2NRc, —NRcS(═O)2N(Rc)2, —P(Rc)2, —P(═O)(Rd)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, each of (two R7a, two R61, two R63, two R65, two R66, two R68, two R71, two R73, two R25, two R77, two R81, and two R83) independently together with the nitrogen atom to which they are both attached forms a 3-20 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein, said 3-20 membered heterocyclic ring or 5-10 membered heteroaryl ring is optionally independently substituted with one or more R16w;
Each of (R62, R64, R62, R69, R72, R74, R76, R28, R82 and R84) at each occurrence is independently selected from hydrogen, deuterium, —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, haloC2-10alkenyl, —C2-10alkynyl, haloC2-10alkynyl, —N(Rb)2, —ORb, —SRb, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-10alkyl, haloC1-10alkyl, haloC1-10alkoxy, —C2-10alkenyl, —C2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —N(Rc)2, —ORc, —SR, —S(═O)Rd, —S(═O)2Rd, —C(═O)Rd, —C(═O)OR, —OC(═O)Rd, —C(═O)N(Rc)2, —NRcC(═O)Rd, —OC(═O)ORc, —NRcC(═O)ORd, —OC(═O)N(Rc)2, —NRcC(═O)N(Rc)2, —S(═O)ORc, —OS(═O)Rd, —S(═O)N(Rc)2, —NRcS(═O)Rd, —S(═O)2ORc, —OS(═O)2Rd, —S(═O)2N(Rc)2, —NRcS(═O)2Rd, —OS(═O)2ORc, —NRcS(═O)2ORc, —OS(═O)2NRc, —NRcS(═O)2N(Rc)2, —P(Rc)2, —P(═O)(Rd)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Each of (Ra, Rb, Rc and Rd) at each occurrence is independently selected from hydrogen, deuterium, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more R16x;
Optionally, each of (two Ra, two Rb and two Rc) independently together with the atom to which they are both attached forms a 3-6 membered heterocyclic ring, wherein said 3-6 membered heterocyclic ring is independently optionally substituted with one or more R16y;
Each of (R16c, R16d, R16e, R16n, R16o, R16p, R16q, R16r, R16s, R16t, R16u, R16v, R16w, R16x and R16y) at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6 alkyl)C(═O)(C1-6alkyl), —OC(═O)O(C1-6alkyl), —NHC(═O)(OC1-6alkyl), —N(C1-6alkyl)C(═O)(OC1-6alkyl), —OC(═O)NH(C1-6alkyl), —OC(═O)N(C1-6alkyl)2, —NHC(═O)NH2, —NHC(═O)NH(C1-6alkyl), —NHC(═O)N(C1-6 alkyl)2, —N(C1-6alkyl)C(═O)NH2, —N(C1-6alkyl)C(═O)NH(C1-6alkyl), —N(C1-6alkyl)C(═O)N(C1-6alkyl)2, —S(═O)(OC1-6alkyl), —OS(═O)(C1-6alkyl), —S(═O)NH2, —S(═O)NH(C1-6alkyl), —S(═O)N(C1-6alkyl)2, —NHS(═O)(C1-6 alkyl), —N(C1-6alkyl)S(═O)(C1-6alkyl), —S(═O)2(OC1-6alkyl), —OS(═O)2(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6 alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), —OS(═O)2O(C1-6alkyl), —NHS(═O)2O(C1-6alkyl), —N(C1-6alkyl)S(═O)2O(C1-6alkyl), —OS(═O)2NH2, —OS(═O)2NH(C1-6alkyl), —OS(═O)2N(C1-6alkyl)2, —NHS(═O)2NH2, —NHS(═O)2NH(C1-6alkyl), —NHS(═O)2N(C1-6alkyl)2, —N(C1-6 alkyl)S(═O)2NH2, —N(C1-6alkyl)S(═O)2NH(C1-6alkyl), —N(C1-6alkyl)S(═O)2N(C1-6alkyl)2, —PH(C1-6alkyl), —P(C1-6 alkyl)2, —P(═O)H(C1-6alkyl), —P(═O)(C1-6alkyl)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
wherein, said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —C2-3alkenyl, —C2-3alkynyl, —CN, —NO2, —N3, oxo, —NB2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —O(C1-3alkyl), —SH, —S(C1-3alkyl), —S(═O)(C1-3alkyl), —S(═O)2(C1-3alkyl), —C(═O)(C1-3alkyl), —C(═O)OH, —C(═O)(OC1-3alkyl), —OC(═O)(C1-3alkyl), —C(═O)NH2, —C(═O)NH(C1-3alkyl), —C(═O)N(C1-3alkyl)2, —NHC(═O)(C1-3alkyl), —N(C1-3alkyl)C(═O)(C1-3alkyl), —OC(═O)O(C1-3alkyl), —NHC(═O)(OC1-3alkyl), —N(C1-3alkyl)C(═O)(OC1-3alkyl), —OC(═O)NH(C1-3alkyl), —OC(═O)N(C1-3alkyl)2, —NHC(═O)NH2, —NHC(═O)NH(C1-3alkyl), —NHC(═O)N(C1-3alkyl)2, —N(C1-3alkyl)C(═O)NH2, —N(C1-3alkyl)C(═O)NH(C1-3alkyl), —N(C1-3 alkyl)C(═O)N(C1-3alkyl)2, —S(═O)(OC1-3alkyl), —OS(═O)(C1-3alkyl), —S(═O)NH2, —S(═O)NH(C1-3alkyl), —S(═O)N(C1-3alkyl)2, —NHS(═O)(C1-3alkyl), —N(C1-3alkyl)S(═O)(C1-3alkyl), —S(═O)2(OC1-3alkyl), —OS(═O)2(C1-3alkyl), —S(═O)2NH2, —S(═O)2NH(C1-3alkyl), —S(═O)2N(C1-3alkyl)2, —NHS(═O)2(C1-3alkyl), —N(C1-3 alkyl)S(═O)2(C1-3alkyl), —OS(═O)2O(C1-3alkyl), —NHS(═O)2O(C1-3alkyl), —N(C1-3alkyl)S(═O)2O(C1-3alkyl), —OS(═O)2NH2, —OS(═O)2NH(C1-3alkyl), —OS(═O)2N(C1-3alkyl)2, —NHS(═O)2NH2, —NHS(═O)2NH(C1-3alkyl), —NHS(═O)2N(C1-3alkyl)2, —N(C1-3alkyl)S(═O)2NH2, —N(C1-3alkyl)S(═O)2NH(C1-3alkyl), —N(C1-3alkyl)S(═O)2N(C1-3alkyl)2, —PH(C1-3alkyl), —P(C1-3alkyl)2, —P(═O)H(C1-3alkyl), —P(═O)(C1-3alkyl)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6 membered aryl or 5-6 membered heteroaryl;
Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(═O) or S(═O)2.
60. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, the compound is selected from any one of the following formulas:
Figure US20240376128A1-20241114-C01343
Figure US20240376128A1-20241114-C01344
Wherein:
RS1 linked with the carbon atom indicated with ** and NR2a linked with the carbon atom indicated with * are in a trans configuration;
RS1 linked with the carbon atom indicated with ## and NR2a linked with the carbon atom indicated with # are in a cis configuration.
61. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, R2a is selected from hydrogen, deuterium, —C1-6alkyl, haloC1-6alkyl, —C1-6alkoxy, —C(═O)C1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2, phenyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; wherein said —C1-6alkyl, haloC1-6alkyl, —C1-6alkoxy, —C(═O)C1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-3alkyl, haloC1-3alkyl, —C2-3alkenyl, —C2-3alkynyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2, phenyl, or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S.
62. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, R2a is selected from any moiety in the Table 1 as shown in the description.
63. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, RS1 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; wherein said —C1-6alkyl, haloC1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3 alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
Optionally, two RS1 together with the carbon atom to which they are both attached form
Figure US20240376128A1-20241114-C01345
a 3-6 membered carbocyclic ring or a 3-6 heterocyclic ring; wherein, said
Figure US20240376128A1-20241114-C01346
3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more substitutents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
Optionally, two adjacent RS1 together with the carbon atoms to which they are respectively attached form a 3-6 membered carbocyclic ring, or a 3-6 membered heterocyclic ring, wherein, each of rings is independently optionally substituted with one or more substitutents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OH, —OC1-3alkyl, —SH, —SC1-3alkyl, —C(═O)C1-3alkyl, —C(═O)OH, —C(═O)OC1-3alkyl, —OC(═O)C1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl.
64. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, the moiety of
Figure US20240376128A1-20241114-C01347
is selected from the moiety in the Table 2 as shown in the description.
65. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, the moiety of
Figure US20240376128A1-20241114-C01348
is selected from the moiety in the Table 3 as shown in the description.
66. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, RS5 at each occurrence is independently selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-3alkenyl, —CN, —N(R66)2, —OR66, —SR66, —C(═O)R67, —C(═O)OR66, —OC(═O)R67, —C(═O)N(R66)2, —NR66C(═O)R67, —OC(═O)OR66, —NR66C(═O)OR66, —OC(═O)N(R66)2, —NR66C(═O)N(R66)2, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S or
Figure US20240376128A1-20241114-C01349
wherein, said —C1-6alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —CN, oxo, —N(R68)2, —OR68, —C(═O)R68, —C(═O)OR68, —OC(═O)R68, —C(═O)N(R68)2, —NR68C(═O)R69, —OC(═O)OR68, —NR68C(═O)OR69, —OC(═O)N(R68)2, —OC(═S)N(R68)2, —NR68C(═O)N(R68)2, —NR68S(═O)2R69, 3-6 membered cycloalkyl or 4-6 membered heterocyclyl; said 4-8 membered heterocyclyl is substituted with 1, 2 or 3 substituents selected from deuterium or —OR68; said haloC1-6alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, —OR68 or —C(═O)OR68; said —C2-3alkenyl is substituted with 1 substituents selected from deuterium or —C(═O)NR68R69;
Optionally, two RS5 together with the carbon atom to which they are both attached form
Figure US20240376128A1-20241114-C01350
Each of (R66 or R67) is independently selected from hydrogen; deuterium; —C1-6alkyl; haloC1-6alkyl; or —C1-6alkyl substituted with 1 or 2 substituents selected from —C(═O)N(C1-6alkyl)2, —OC1-6alkyl, —C(═O)OC1-6alkyl, —NHC1-6alkyl or —N(C1-6alkyl)2;
Each of (R68 or R69) is independently selected from hydrogen; deuterium; —C1-6alkyl; haloC1-6alkyl; 5 membered heteroaryl; cyclopropyl; cyclopentyl; cyclohexyl; 5 membered heterocyclyl; 6 membered heterocyclyl; 5-membered heteroaryl; 6 membered heteroaryl; or —C1-6alkyl substituted with 1, or 2 substituents selected from deuterium, —OC1-6alkyl, —NHC1-6alkyl, —N(C1-6alkyl)2 or —C(═O)N(C1-6alkyl)2; wherein said 5 membered heteroaryl, cyclopropyl, cyclopentyl, cyclohexyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5-membered heteroaryl or 6 membered heteroaryl is optionally substituted with 1 or 2 substitutents selected from deuterium, —C1-3alkyl, —OH, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, —OC1-3alkyl or cyclopropyl;
Optionally, two R66 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring;
Optionally, two R68 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring.
67. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, RS5 at each occurrence is independently selected from deuterium, —F, —Cl, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH═CH2, —C═CH, —C═CCH3, —C═CD, —CH2C═CH, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH2CH2F, —CH2CH2CH2F, —OH, —CH2OH, —CH2CH2OH, —OCH3, —OC(CH3)2, —OCH2CH3, —OCH(CH3)2, —OCF3, —SH, —SCH3, —SCF3, —C(═O)CF3, —CN, —NH2, —N(CH3)2, —NHCH2CH3, —CH2N(CH3)2, —NHC(═O)CH3, —NHC(═O)OCH3, —CH2NHC(═O)OCH3, —OC(═O)NHCH3, —OC(═O)N(CH3)2, —CH2OC(═O)N(CH3)2, —CH2OC(═O)NHCH3, —NHC(═O)N(CH3)2, —CH2NHC(═O)N(CH3)2, —CH2NHC(═O)CH3, —CH2OCH3, or
Figure US20240376128A1-20241114-C01351
68. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, q5 is selected from 0 or 1.
69. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, the moiety of
Figure US20240376128A1-20241114-C01352
is selected from any moiety in the Table 4 as shown in the description.
70. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, R4 is selected from any moiety in the Table 6 as shown in the description;
Wherein, each moiety in the Table 6 is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R41.
71. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, R41 is independently selected from —F, —Cl, —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —C2-3alkenyl, —C2-3alkynyl, —CN, —NH2, —NH(C1-3alkyl), —N(C1-3 alkyl)2, —OH, —O(C1-3alkyl), —SH, —S(C1-3alkyl), —S(═O)H, —S(═O)(C1-3alkyl), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein said —C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, —C2-3alkenyl, —C2-6alkynyl, —NH2, —SH, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is independently optionally substituted with 1, 2 or 3 R42;
Each of R42 is independently selected from —F; —C1-3alkyl; haloC1-3alkyl; —CN; —OH; —NH2; —NH(C1-3alkyl); —N(C1-3alkyl)2; —OC1-3alkyl; 3-6 membered cycloalkyl; or —C1-3alkyl substituted with 1, 2 or 3 substituents selected from —F, haloC1-3alkyl, —CN, —OH, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2 or —OC1-3alkyl.
72. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, R4 is selected from any moiety in the Table 9 as shown in the description.
73. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, R51 is selected from hydrogen, deuterium, —Cl, —CN, —CH3, —CHF2, —CH2F, —CF3, —CH2OH, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —NHCH3, —N(CH3)2, —OCF3, —CN, —CH2CN, —COOH, —CONH2, —COOCH3,
Figure US20240376128A1-20241114-C01353
74. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, R52 is selected from —F.
75. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, the prodrug is selected from any one of the following formulas:
Figure US20240376128A1-20241114-C01354
R43 at each occurrence is independently selected from
Figure US20240376128A1-20241114-C01355
R4c is selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R4j;
R4d and R4e are each selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C(═O)C1-6alkyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R4j;
R4f and R4g are each selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C(═O)C1-6alkyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R4j;
R4h, R4i, R4m, R4n and R4p are each selected from hydrogen, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6 alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6 alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, R4f and R4g together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2 and optionally substituted with one or more R4;
Optionally, R4f and R4h together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteroatoms selected from N, O, S, S(═O) or S(═O)2 and optionally substituted with one or more R4;
R4j at each occurrence is independently selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, oxo, —NO2, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(C1-6 alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6 alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 substituents selected from halogen; —C1-6alkyl; haloC1-6alkyl; —CN; oxo; —OH; —NH2; —NH(C1-6alkyl); —N(C1-6alkyl)2; —OC1-6alkyl; or —C1-6alkyl substituted with 1, 2 or 3 substituents selected from halogen, haloC1-6alkyl, —CN, —OH, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2 or —OC1-6alkyl;
Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(═O) or S(═O)2.
76. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, wherein, the moiety of
Figure US20240376128A1-20241114-C01356
is selected from any moiety in the Table 12 as shown in the description.
77. The compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59 selected from any compound in the Table 13 as shown in the description.
78. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of Formula (IB), the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 59, and a pharmaceutically acceptable excipient.
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